89 results on '"Miriam Zacchia"'
Search Results
2. Diffusion tensor imaging for the study of early renal dysfunction in patients affected by bardet-biedl syndrome
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Pasquale Borrelli, Miriam Zacchia, Carlo Cavaliere, Luca Basso, Marco Salvatore, Giovambattista Capasso, and Marco Aiello
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Medicine ,Science - Abstract
Abstract Kidney structural abnormalities are common features of Bardet-Biedl syndrome (BBS) patients that lead to a progressive decline in renal function. Magnetic resonance diffusion tensor imaging (DTI) provides useful information on renal microstructures but it has not been applied to these patients. This study investigated using DTI to detect renal abnormalities in BBS patients with no overt renal dysfunction. Ten BBS subjects with estimated glomerular filtration rates over 60 ml/min/1.73m2 and 14 individuals matched for age, gender, body mass index and renal function were subjected to high-field DTI. Fractional anisotropy (FA), and mean, radial and axial diffusivity were evaluated from renal cortex and medulla. Moreover, the corticomedullary differentiation of each DTI parameter was compared between groups. Only cortical FA statistically differed between BBS patients and controls (p = 0.033), but all the medullary DTI parameters discriminated between the two groups with lower FA (p
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- 2021
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3. Metabolomic fingerprinting of renal disease progression in Bardet-Biedl syndrome reveals mitochondrial dysfunction in kidney tubular cells
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Emanuela Marchese, Marianna Caterino, Davide Viggiano, Armando Cevenini, Salvatore Tolone, Ludovico Docimo, Valentina Di Iorio, Francesca Del Vecchio Blanco, Roberta Fedele, Francesca Simonelli, Alessandra Perna, Vincenzo Nigro, Giovambattista Capasso, Margherita Ruoppolo, and Miriam Zacchia
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Pathophysiology ,metabolomics ,Science - Abstract
Summary: Chronic kidney disease (CKD) is a major clinical sign of patients with Bardet-Biedl syndrome (BBS), especially in those carrying BBS10 mutations. Twenty-nine patients with BBS and 30 controls underwent a serum-targeted metabolomic analysis. In vitro studies were conducted in two kidney-derived epithelial cell lines, where Bbs10 was stably deleted (IMCD3-Bbs10−/−cells) and over-expressed. The CKD status affected plasmatic metabolite fingerprinting in both patients with BBS and controls. Specific phosphatidylcholine and acylcarnitines discriminated eGFR decline only in patients with BBS. IMCD3-Bbs10−/ cells displayed intracellular lipidaccumulation, reduced mitochondrial potential membrane and citrate synthase staining. Mass-Spectrometry-based analysis revealed that human BBS10 interacted with six mitochondrial proteins, in vitro. In conclusion, renal dysfunction correlated with abnormal phosphatidylcholine and acylcarnitines plasma levels in patients with BBS; in vitro, Bbs10 depletion caused mitochondrial defects while human BBS10 interacted with several mitochondria-related proteins, suggesting an unexplored role of this protein.
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- 2022
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4. Next-Generation Sequencing (NGS) Analysis Illustrates the Phenotypic Variability of Collagen Type IV Nephropathies
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Miriam Zacchia, Giovanna Capolongo, Francesca Del Vecchio Blanco, Floriana Secondulfo, Neha Gupta, Giancarlo Blasio, Rosa Maria Pollastro, Angela Cervesato, Giulio Piluso, Giuseppe Gigliotti, Annalaura Torella, Vincenzo Nigro, Alessandra F. Perna, Giovambattista Capasso, and Francesco Trepiccione
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basal membrane ,COL4 ,kidney disease ,NGS ,Genetics ,QH426-470 - Abstract
Mutations in COL4A3-A5 cause a spectrum of glomerular disorders, including thin basement membrane nephropathy (TBMN) and Alport syndrome (AS). The wide application of next-generation sequencing (NGS) in the last few years has revealed that mutations in these genes are not limited to these clinical entities. In this study, 176 individuals with a clinical diagnosis of inherited kidney disorders underwent an NGS-based analysis to address the underlying cause; those who changed or perfected the clinical diagnosis after molecular analysis were selected. In 5 out of 83 individuals reaching a molecular diagnosis, the genetic result was unexpected: three individuals showed mutations in collagen type IV genes. These patients showed the following clinical pictures: (1) familial focal segmental glomerulosclerosis; (2) end-stage renal disease (ESRD) diagnosed incidentally in a 49-year-old man, with diffuse cortical calcifications on renal imaging; and (3) dysmorphic and asymmetric kidneys with multiple cysts and signs of tubule–interstitial defects. Genetic analysis revealed rare heterozygote/compound heterozygote COL4A4-A5 variants. Our study highlights the key role of NGS in the diagnosis of inherited renal disorders and shows the phenotype variability in patients carrying mutations in collagen type IV genes.
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- 2023
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5. Exploring Key Challenges of Understanding the Pathogenesis of Kidney Disease in Bardet–Biedl Syndrome
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Emanuela Marchese, Margherita Ruoppolo, Alessandra Perna, Giovambattista Capasso, and Miriam Zacchia
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Bardet–Biedl syndrome ,ciliopathies ,genetics ,kidney disease ,physiopathology ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Bardet–Biedl syndrome (BBS) is a rare pleiotropic inherited disorder known as a ciliopathy. Kidney disease is a cardinal clinical feature; however, it is one of the less investigated traits. This study is a comprehensive analysis of the literature aiming to collect available information providing mechanistic insights into the pathogenesis of kidney disease by analyzing clinical and basic science studies focused on this issue. The analysis revealed that the syndrome is either clinically and genetically heterogenous, with 24 genes discovered to date, but with 3 genes (BBS1, BBS2, and BBS10) accounting for almost 50% of diagnoses; genotype–phenotype correlation studies showed that patients with BBS1 mutations have a less severe renal phenotype than the other 2 most common loci; in addition, truncating rather than missense mutations are more likely to cause kidney disease. However, significant intrafamilial clinical variability has been described, with no clear explanation to date. In mice kidneys, Bbs genes have relative low expression levels, in contrast with other common affected organs, like the retina; surprisingly, Bbs1 is the only locus with basal overexpression in the kidney. In vitro studies indicate that signalling pathways involved in embryonic kidney development and repair are affected in the context of BBS depletion; in mice, kidney disease does not have a full penetrance; when present, it resembles human phenotype and shows an age-dependent progression. Data on the exact contribution of local versus systemic consequences of Bbs dysfunction are scanty and further investigations are required to get firm conclusions.
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- 2020
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6. Urinary Metabolic Profile of Patients with Transfusion-Dependent β-Thalassemia Major Undergoing Deferasirox Therapy
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Giovanna Capolongo, Miriam Zacchia, Amerigo Beneduci, Silvia Costantini, Patrizia Cinque, Anna Spasiano, Giuseppina De Luca, Maria Enrica Di Pietro, Paolo Ricchi, Francesco Trepiccione, Giovambattista Capasso, and Aldo Filosa
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β-thalassemia major ,metabolomics ,urinomics ,tubular function ,renal disease ,Dermatology ,RL1-803 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Introduction: Renal dysfunction is a frequent complication in patients suffering from β-thalassemia major (β-TM). The aim of this study was to analyze the renal function and urine metabolomic profile of β-TM patients undergoing transfusions and deferasirox (DFX) therapy, in order to better characterize and shed light on the pathogenesis of renal disease in this setting. Methods and Subjects: 40 patients affected by β-TM treated with DFX and 35 age- and gender-matched healthy controls were enrolled in the study. Renal function was assessed. Glomerular filtration rate (GFR) was estimated with CKD-EPI and Schwartz formula for adults and children, respectively. Renal tubular function and maximal urine concentration ability were tested. Urine specimens were analyzed by nuclear magnetic resonance spectroscopy to identify the urinary metabolite profiles. Results: The study of renal function in β-TM patients revealed normal estimated (e)GFR mean values and the albumin-to-creatinine ratio was
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- 2020
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7. COVID-19, Low-Molecular-Weight Heparin, and Hemodialysis
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Alessandra F. Perna, Giovanna Capolongo, Francesco Trepiccione, Mariadelina Simeoni, Miriam Zacchia, and Diego Ingrosso
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covid-19 ,low-molecular-weight heparin ,hemodialysis ,Dermatology ,RL1-803 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Diseases of the genitourinary system. Urology ,RC870-923 - Published
- 2020
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8. Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome
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Emanuela Marchese, Marianna Caterino, Roberta Fedele, Francesca Pirozzi, Armando Cevenini, Neha Gupta, Diego Ingrosso, Alessandra Perna, Giovambattista Capasso, Margherita Ruoppolo, and Miriam Zacchia
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Bardet–Biedl syndrome ,urine metabolomics kidney dysfunction ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy resulting in multiple organ dysfunctions, including chronic kidney disease (CKD). Despite the recent progress in the ’ciliopathy’ field, there is still little information on the mechanisms underlying renal disease. To elucidate these pathomechanisms, we conducted a translational study, including (i) the characterization of the urine metabolomic pattern of BBS patients and controls in a pilot and confirmation study and (ii) the proteomic analysis of the BBS10 interactome, one of the major mutated BBS genes in patients, in a renal-epithelial-derived cell culture model. The urine metabolomic fingerprinting of BBS patients differed from controls in both pilot and confirmation studies, demonstrating an increased urinary excretion of several monocarboxylates, including lactic acid (LA), at both early and late CKD stages. Increased urine LA was detected in the absence of both increased plasmatic LA levels and generalized proximal tubular dysfunction, suggesting a possible renal-specific defective handling. The inner medulla renal epithelial (IMCD3) cell line, where Bbs10 was stably invalidated, displayed an increased proliferative rate, increased ATP production, and an up-regulation of aerobic glycolysis. A mass spectrometry-based analysis detected several putative BBS10 interactors in vitro, indicating a potential role of BBS10 in several biological processes, including renal metabolism, RNA processing, and cell proliferation. The present study suggests that the urine metabolomic pattern of BBS patients may reflect intra-renal metabolic aberrations. The analysis of BBS10 interactors unveils possible novel functions, including cell metabolism.
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- 2022
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9. Diuretic Resistance in Cardio-Nephrology: Role of Pharmacokinetics, Hypochloremia, and Kidney Remodeling
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Cristina Masella, Davide Viggiano, Ida Molfino, Miriam Zacchia, Giovanna Capolongo, Pietro Anastasio, and Mariadelina Simeoni
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Heart failure ,Diuretic resistance ,Fluid overload ,Vaptans ,Dermatology ,RL1-803 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Background: Diuretic resistance is among the most challenging problems that the cardio-nephrologist must address in daily clinical practice, with a considerable burden on hospital admissions and health care costs. Indeed, loop diuretics are the first-line therapy to overcome fluid overload in heart failure patients. The pathophysiological mechanisms of fluid and sodium retention are complex and depend on several neuro-hormonal signals mainly acting on sodium reabsorption along the renal tubule. Consequently, doses and administration modalities of diuretics must be carefully tailored to patients in order to overcome under- or overtreatment. The frequent and tricky development of diuretic resistance depends in part on post-diuretic sodium retention, reduced tubular secretion of the drug, and reduced sodium/chloride sensing. Sodium and chloride depletions have been recently shown to be major factors mediating these processes. Aquaretics and high-saline infusions have been recently suggested in cases of hyponatremic conditions. This review discusses the limitations and strengths of these approaches. Summary: Long-term diuretic use may lead to diuretic resistance in cardio-renal syndromes. To overcome this complication intravenous administration of loop diuretics and a combination of different diuretic classes have been proposed. In the presence of hyponatremia, high-saline solutions in addition to loop diuretics might be beneficial, whereas aquaretics require caution to avoid overcorrection. Key Messages: Diuretic resistance is a central theme for cardio-renal syndromes. Hyponatremia and hypochloremia may be part of the mechanisms for diuretic resistance. Aquaretics and high-saline solutions have been proposed as possible new therapeutic solutions.
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- 2019
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10. Urine Proteomics Revealed a Significant Correlation Between Urine-Fibronectin Abundance and Estimated-GFR Decline in Patients with Bardet-Biedl Syndrome
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Marianna Caterino, Miriam Zacchia, Michele Costanzo, Giuliana Bruno, Davide Arcaniolo, Francesco Trepiccione, Rosa Anna Siciliano, Maria Fiorella Mazzeo, Margherita Ruoppolo, and Giovambattista Capasso
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Bardet-Biedl Syndrome ,Kidney dysfunction ,Urine proteome ,Fibronectin ,GFR decline ,Dermatology ,RL1-803 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Background:/Aims: Renal disease is a common cause of morbidity in patients with Bardet-Biedl syndrome (BBS), however the severity of kidney dysfunction is highly variable. To date, there is little information on the pathogenesis, the risk and predictor factors for poor renal outcome in this setting. The present study aims to analyze the spectrum of urinary proteins in BBS patients, in order to potentially identify 1) disease-specific proteomic profiles that may differentiate the patients from normal subjects; 2) urinary markers of renal dysfunction. Methods: Fourteen individuals (7 males and 7 females) with a clinical diagnosis of BBS have been selected in this study. A pool of 10 aged-matched males and 10 aged-matched females have been used as controls for proteomic analysis. The glomerular filtration rate (eGFR) has been estimated using the CKD-EPI formula. Variability of eGFR has been retrospectively assessed calculating average annual eGFR decline (ΔeGFR) in a mean follow-up period of 4 years (3-7). Results: 42 proteins were significantly over- or under-represented in BBS patients compared with controls; the majority of these proteins are involved in fibrosis, cell adhesion and extracellular matrix organization. Statistic studies revealed a significant correlation between urine fibronectin (u-FN) (r2=0.28; p
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- 2018
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11. Impact of Local and Systemic Factors on Kidney Dysfunction in Bardet-Biedl Syndrome
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Miriam Zacchia, Giovanna Capolongo, Francesco Trepiccione, and Vincent Marion
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Bardet-Biedl ,Kidney Defects ,Primary Cilium ,Dermatology ,RL1-803 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Bardet Biedl syndrome (BBS) is a rare inherited syndromic condition characterized by renal and extra-renal disorders. Renal defect, at either structural or functional level, is one of the cardinal clinical features, and is a major cause of morbidity. However, the pathogenic mechanism underlying its dysfunction remains largely unknown, and to date only symptomatic treatment with no specific therapy is available for these patients. Elucidating aberrant cellular and/or systemic processes that impact kidney function is therefore a prerequisite to develop targeted innovative therapeutic strategies for the BBS patients. Given the proven role of BBS proteins in the function of the primary cilium (PC) and considering the clinical overlapping of BBS with other ciliopathies, BBS is considered the result of disruption of ciliary activities. The present review aims at giving an updated overview of the spectrum of renal abnormalities in BBS patients according to the existing scientific literature, and discusses the possible role of intrinsic PC dysfunction into the pathogenesis of renal defects based on the most recent findings demonstrating a possible role of systemic factors in favoring the progression of renal disease.
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- 2017
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12. ERK1,2 Signalling Pathway along the Nephron and Its Role in Acid-base and Electrolytes Balance
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Giovanna Capolongo, Yoko Suzumoto, Mariavittoria D’Acierno, Mariadelina Simeoni, Giovambattista Capasso, and Miriam Zacchia
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MAPK ,ERK1,2 ,cell signaling ,acid-base ,electrolytes ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.
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- 2019
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13. Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium
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Carmela Vigorito, Evgeniya Anishchenko, Luigi Mele, Giovanna Capolongo, Francesco Trepiccione, Miriam Zacchia, Patrizia Lombari, Rosanna Capasso, Diego Ingrosso, and Alessandra F. Perna
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lanthionine ,glutathione ,uremic toxin ,chronic kidney disease ,H2S ,sulfane sulfur ,CBS ,CSE ,VEGFA ,calcium homeostasis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-β-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.
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- 2019
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14. Zebrafish, a Novel Model System to Study Uremic Toxins: The Case for the Sulfur Amino Acid Lanthionine
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Alessandra F. Perna, Evgeniya Anishchenko, Carmela Vigorito, Miriam Zacchia, Francesco Trepiccione, Salvatore D’Aniello, and Diego Ingrosso
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uremic toxin ,lanthionine ,uremia ,dialysis ,cardiovascular disease ,zebrafish ,glutathione ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The non-proteinogenic amino acid lanthionine is a byproduct of hydrogen sulfide biosynthesis: the third endogenous vasodilator gas, after nitric oxide and carbon monoxide. While hydrogen sulfide is decreased in uremic patients on hemodialysis, lanthionine is increased and has been proposed as a new uremic toxin, since it is able to impair hydrogen sulfide production in hepatoma cells. To characterize lanthionine as a uremic toxin, we explored its effects during the early development of the zebrafish (Danio rerio), a widely used model to study the organ and tissue alterations induced by xenobiotics. Lanthionine was employed at concentrations reproducing those previously detected in uremia. Light-induced visual motor response was also studied by means of the DanioVision system. Treatment of zebrafish embryos with lanthionine determined acute phenotypical alterations, on heart organogenesis (disproportion in cardiac chambers), increased heart beating, and arrhythmia. Lanthionine also induced locomotor alterations in zebrafish embryos. Some of these effects could be counteracted by glutathione. Lanthionine exerted acute effects on transsulfuration enzymes and the expression of genes involved in inflammation and metabolic regulation, and modified microRNA expression in a way comparable with some alterations detected in uremia. Lanthionine meets the criteria for classification as a uremic toxin. Zebrafish can be successfully used to explore uremic toxin effects.
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- 2018
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15. The Sulfur Metabolite Lanthionine: Evidence for a Role as a Novel Uremic Toxin
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Alessandra F. Perna, Miriam Zacchia, Francesco Trepiccione, and Diego Ingrosso
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lanthionine ,homolanthionine ,hydrogen sulfide ,homocysteine ,hemodialysis ,uremic toxins ,Medicine - Abstract
Lanthionine is a nonproteinogenic amino acid, composed of two alanine residues that are crosslinked on their β-carbon atoms by a thioether linkage. It is biosynthesized from the condensation of two cysteine molecules, while the related compound homolanthionine is formed from the condensation of two homocysteine molecules. The reactions can be carried out by either cystathionine-β-synthase (CBS) or cystathionine-γ-lyase (CSE) independently, in the alternate reactions of the transsulfuration pathway devoted to hydrogen sulfide biosynthesis. Low plasma total hydrogen sulfide levels, probably due to reduced CSE expression, are present in uremia, while homolanthionine and lanthionine accumulate in blood, the latter several fold. Uremic patients display a derangement of sulfur amino acid metabolism with a high prevalence of hyperhomocysteinemia. Uremia is associated with a high cardiovascular mortality, the causes of which are still not completely explained, but are related to uremic toxicity, due to the accumulation of retention products. Lanthionine inhibits hydrogen sulfide production in hepatoma cells, possibly through CBS inhibition, thus providing some basis for the biochemical mechanism, which may significantly contribute to alterations of metabolism sulfur compounds in these subjects (e.g., high homocysteine and low hydrogen sulfide). We therefore suggest that lanthionine is a novel uremic toxin.
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- 2017
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16. Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook
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Andrea Melluso, Floriana Secondulfo, Giovanna Capolongo, Giovambattista Capasso, Miriam Zacchia, Melluso, A, Secondulfo, F, Capolongo, G, Capasso, G, and Zacchia, M
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Chemical Health and Safety ,Pharmacology (medical) ,General Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Safety Research - Published
- 2023
17. miRNA-23a modulates sodium-hydrogen exchanger 1 expression: studies in medullary thick ascending limb of salt-induced hypertensive rats
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Patrizia Lombari, Massimo Mallardo, Oriana Petrazzuolo, Joseph Amruthraj Nagoth, Giuseppe Fiume, Roberto Scanni, Anna Iervolino, Sara Damiano, Annapaola Coppola, Margherita Borriello, Diego Ingrosso, Alessandra F Perna, Miriam Zacchia, Francesco Trepiccione, Giovambattista Capasso, Lombari, Patrizia, Mallardo, Massimo, Petrazzuolo, Oriana, Nagoth, Joseph Amruthraj, Fiume, Giuseppe, Scanni, Roberto, Iervolino, Anna, Damiano, Sara, Coppola, Annapaola, Borriello, Margherita, Ingrosso, Diego, Perna, Alessandra, Zacchia, Miriam, Trepiccione, Francesco, Capasso, Giovambattista, Amruthraj Nagoth, Joseph, Perna, Alessandra F., and Capasso., Francesco Trepiccione and Giovambattista
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Transplantation ,Nephrology ,Thick Ascending Limb ,high sodium, miRNA-23a, miRNA pro ling, NHE1, thick ascending limb ,miRNA-23a ,NHE1 ,miRNA profiling ,high sodium - Abstract
Background The kidney is the main organ in the pathophysiology of essential hypertension. Although most bicarbonate reabsorption occurs in the proximal tubule, the medullary thick ascending limb (mTAL) of the nephron also maintains acid–base balance by contributing to 25% of bicarbonate reabsorption. A crucial element in this regulation is the sodium-hydrogen exchanger 1 (NHE1), a ubiquitous membrane protein controlling intracellular pH, where proton extrusion is driven by the inward sodium flux. MicroRNA (miRNA) expression of hypertensive patients significantly differs from that of normotensive subjects. The aim of this study was to determine the functional role of miRNA alterations at the mTAL level. Methods By miRNA microarray analysis, we identified miRNA expression profiles in isolated mTALs from high sodium intake–induced hypertensive rats (HSD) versus their normotensive counterparts (NSD). In vitro validation was carried out in rat mTAL cells. Results Five miRNAs involved in the onset of salt-sensitive hypertension were identified, including miR-23a, which was bioinformatically predicted to target NHE1 mRNA. Data demonstrated that miRNA-23a is downregulated in the mTAL of HSD rats while NHE1 is upregulated. Consistently, transfection of an miRNA-23a mimic in an mTAL cell line, using a viral vector, resulted in NHE1 downregulation. Conclusion NHE1, a protein involved in sodium reabsorption at the mTAL level and blood pressure regulation, is upregulated in our model. This was due to a downregulation of miRNA-23a. Expression levels of this miRNA are influenced by high sodium intake in the mTALs of rats. The downregulation of miRNA-23a in humans affected by essential hypertension corroborate our data and point to the potential role of miRNA-23a in the regulation of mTAL function following high salt intake.
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- 2022
18. Correction: Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria
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Judy Savige, Helen Storey, Elizabeth Watson, Jens Michael Hertz, Constantinos Deltas, Alessandra Renieri, Francesca Mari, Pascale Hilbert, Pavlina Plevova, Peter Byers, Agne Cerkauskaite, Martin Gregory, Rimante Cerkauskiene, Danica Galesic Ljubanovic, Francesca Becherucci, Carmela Errichiello, Laura Massella, Valeria Aiello, Rachel Lennon, Louise Hopkinson, Ania Koziell, Adrian Lungu, Hansjorg Martin Rothe, Julia Hoefele, Miriam Zacchia, Tamara Nikuseva Martic, Asheeta Gupta, Albertien van Eerde, Susie Gear, Samuela Landini, Viviana Palazzo, Laith al-Rabadi, Kathleen Claes, Anniek Corveleyn, Evelien Van Hoof, Micheel van Geel, Maggie Williams, Emma Ashton, Hendica Belge, Elisabeth Ars, Agnieszka Bierzynska, Concetta Gangemi, and Beata S. Lipska-Ziętkiewicz
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Genetics ,Genetics (clinical) - Published
- 2023
19. A case series of adult patients affected by EAST/SeSAME syndrome suggests more severe disease in subjects bearing KCNJ10 truncating mutations
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Rosa Giunta, Giovambattista Capasso, Giovanna Capolongo, Luciano Gervasi, Francesco Trepiccione, Miriam Zacchia, Gianpiero Toriello, Mariadelina Simeoni, Yoko Suzumoto, Valeria Columbano, Gabriele Trimarchi, Alessandra F. Perna, Teresa Mattina, Rosa Maria Pollastro, and Francesco Rapisarda
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0301 basic medicine ,Mutation ,medicine.medical_specialty ,biology ,business.industry ,General Medicine ,KCNJ10 ,Disease ,030105 genetics & heredity ,medicine.disease_cause ,medicine.disease ,Gastroenterology ,Frameshift mutation ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Tubulopathy ,Internal medicine ,biology.protein ,Medicine ,Missense mutation ,business ,030217 neurology & neurosurgery ,Rare disease - Abstract
EAST/SeSAME syndrome is a rare disease affecting the Central Nervous System (CNS), inner ear, and kidney. The syndrome is due to loss-of-function mutations in the KCNJ10 gene encoding the inward-rectifying potassium channel Kir4.1. EAST/SeSAME syndrome is mainly diagnosed during childhood with a tonic-clonic seizure being the usual first symptom. Due to a limited number of patients and recent identification of the disease, few data are available on the clinical progress of this disease in adulthood. In particular, neurologic and nephrological outcomes have not been reported. We present a case series of 4 adult patients harbouring homozygous missense mutation p.Ala167Val and homozygous frameshift mutations p.Asn232Glnfs*14 and p.Gly275Valfs*7. Effects of these mutations were predicted by in silico modelling and bioinformatic tools. Patients with truncating mutations were associated with more severe outcomes, both in tubulopathy severity and neurological symptomatology. Conversely, either missense or truncating mutations were correlated with similar severity of epilepsy, with a long free-of-event period up to 20 years old. No eGFR decline was documented. Modelling predicted that truncating mutations lead to complete Kir4.1 dysfunction. Finally, all patients had a mild increase in urinary protein excretion. Our study indicates that the prognosis of patients suffering from EAST/SeSAME syndrome is related to the severity of the mutation causing the disease. As predicted by in silico modelling, truncating mutations of KCNJ10 are associated with more severe disease, with recurrence of symptomatic hypokalemia and more severe neurological phenotype. The type of mutation should be considered for the therapy tailored to patients' phenotype.
- Published
- 2021
20. Urinary proteomics reveals key markers of salt sensitivity in hypertensive patients during saline infusion
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Francesco Trepiccione, Marco Simonini, Paolo Manunta, Angela Bachi, Miriam Zacchia, Vittoria Matafora, Laura Zagato, Chiara Lanzani, Giovambattista Capasso, Matafora, V., Lanzani, C., Zagato, L., Manunta, P., Zacchia, M., Trepiccione, F., Simonini, M., Capasso, G., and Bachi, A.
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Proteomics ,Epithelial sodium channel ,medicine.medical_specialty ,medicine.medical_treatment ,Urinary system ,Sodium ,030232 urology & nephrology ,chemistry.chemical_element ,Salt homeostasis ,Blood Pressure ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Quantitative proteomic ,Renin–angiotensin system ,Quantitative proteomics ,medicine ,Humans ,Sodium Chloride, Dietary ,Saline ,Urokinase ,Salt homeostasi ,Renal sodium reabsorption ,business.industry ,Sodium transporters ,Salt-sensitive hypertension ,Endocrinology ,chemistry ,Nephrology ,Hypertension ,Glutamyl aminopeptidase ,Renin-angiotensin system ,business ,medicine.drug - Abstract
Background: Hypertension is a complex disease and is the major cause of cardiovascular complications. In the vast majority of individuals, the aetiology of elevated blood pressure (BP) cannot be determined, thus impairing optimized therapies and prognosis for individual patients. A more precise understanding of the molecular pathogenesis of hypertension remains a pressing priority for both basic and translational research. Here we investigated the effect of salt on naive hypertensive patients in order to better understand the salt intake-blood pressure relationship. Methods: Patients underwent an acute saline infusion and were defined as salt-sensitive or salt-resistant according to mean blood pressure changes. Urinary proteome changes during the salt load test were analysed by a label-free quantitative proteomics approach. Results: Our data show that salt-sensitive patients display equal sodium reabsorption as salt-resistant patients, as major sodium transporters show the same behaviour during the salt load. However, salt-sensitive patients regulate the renin angiotensin system (RAS) differently from salt-resistant patients, and upregulate proteins, as epidermal growth factor (EGF) and plasminogen activator, urokinase (PLAU), involved in the regulation of epithelial sodium channel ENaC activity. Conclusions: Salt-sensitive and salt-resistant subjects have similar response to a saline/volume infusion as detected by urinary proteome. However, we identified glutamyl aminopeptidase (ENPEP), PLAU, EGF and Xaa-Pro aminopeptidase 2 precursor XPNPEP2 as key molecules of salt-sensitivity, through modulation of ENaC-dependent sodium reabsorption along the distal tubule. Graphic abstract: [Figure not available: see fulltext.].
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- 2021
21. Bardet-Biedl syndrome: The pleiotropic role of the chaperonin-like BBS6, 10, and 12 proteins
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Neha Gupta, Mariavittoria D'Acierno, Enrica Zona, Giovambattista Capasso, Miriam Zacchia, Gupta, N., D'Acierno, M., Zona, E., Capasso, G., and Zacchia, M.
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congenital, hereditary, and neonatal diseases and abnormalities ,Bardet–Biedl syndrome ,BBS6/MKKS ,Chaperonins ,BBS10 ,Group II Chaperonins ,macromolecular substances ,chaperonopathies ,BBS12 and ciliopathie ,chaperonin-like protein ,Mutation ,Genetics ,Humans ,Bardet-Biedl Syndrome ,Genetics (clinical) - Abstract
Bardet–Biedl syndrome (BBS) is a rare pleiotropic disorder known as a ciliopathy. Despite significant genetic heterogeneity, BBS1 and BBS10 are responsible for major diagnosis in western countries. It is well established that eight BBS proteins, namely BBS1, 2, 4, 5, 7, 8, 9, and 18, form the BBSome, a multiprotein complex serving as a regulator of ciliary membrane protein composition. Less information is available for BBS6, BBS10, and BBS12, three proteins showing sequence homology with the CCT/TRiC family of group II chaperonins. Even though their chaperonin function is debated, scientific evidence demonstrated that they are required for initial BBSome assembly in vitro. Recent studies suggest that genotype may partially predict clinical outcomes. Indeed, patients carrying truncating mutations in any gene show the most severe phenotype; moreover, mutations in chaperonin-like BBS proteins correlated with severe kidney impairment. This study is a critical review of the literature on genetics, expression level, cellular localization and function of BBS proteins, focusing primarily on the chaperonin-like BBS proteins, and aiming to provide some clues to understand the pathomechanisms of disease in this setting.
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- 2022
22. Guidelines for genetic testing and management of Alport syndrome
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Judy Savige, Beata S. Lipska-Zietkiewicz, Elizabeth Watson, Jens Michael Hertz, Constantinos Deltas, Francesca Mari, Pascale Hilbert, Pavlina Plevova, Peter Byers, Agne Cerkauskaite, Martin Gregory, Rimante Cerkauskiene, Danica Galesic Ljubanovic, Francesca Becherucci, Carmela Errichiello, Laura Massella, Valeria Aiello, Rachel Lennon, Louise Hopkinson, Ania Koziell, Adrian Lungu, Hansjorg Martin Rothe, Julia Hoefele, Miriam Zacchia, Tamara Nikuseva Martic, Asheeta Gupta, Albertien van Eerde, Susie Gear, Samuela Landini, Viviana Palazzo, Laith al-Rabadi, Kathleen Claes, Anniek Corveleyn, Evelien Van Hoof, Micheel van Geel, Maggie Williams, Emma Ashton, Hendica Belge, Elisabet Ars, Agnieszka Bierzynska, Concetta Gangemi, Alessandra Renieri, Helen Storey, Frances Flinter, Savige, J, Lipska-Zietkiewicz, B, Watson, E, Hertz, Jm, Deltas, C, Mari, F, Hilbert, P, Plevova, P, Byers, P, Cerkauskaite, A, Gregory, M, Cerkauskiene, R, Ljubanovic, Dg, Becherucci, F, Errichiello, C, Massella, L, Aiello, V, Lennon, R, Hopkinson, L, Koziell, A, Lungu, A, Rothe, Hm, Hoefele, J, Zacchia, M, Martic, Tn, Gupta, A, van Eerde, A, Gear, S, Landini, S, Palazzo, V, Al-Rabadi, L, Claes, K, Corveleyn, A, Van Hoof, E, van Geel, M, Williams, M, Ashton, E, Belge, H, Ars, E, Bierzynska, A, Gangemi, C, Renieri, A, Storey, H, Flinter, F., RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and MUMC+: DA KG Lab Centraal Lab (9)
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Feature ,Collagen Type IV ,KIDNEY-TRANSPLANTATION ,RENAL-FAILURE ,MICROSCOPIC HEMATURIA ,Epidemiology ,Nephritis, Hereditary ,Alport syndrome ,COL4A3 ,COL4A4 ,COL4A5 ,FSGS ,collagen IV ,digenic Alport syndrome ,genetic testing ,kidney cysts ,thin basement membrane nephropathy ,Critical Care and Intensive Care Medicine ,urologic and male genital diseases ,Autoantigens ,DIGENIC INHERITANCE ,SEQUENCE VARIANTS ,Humans ,GENOTYPE-PHENOTYPE CORRELATIONS ,Transplantation ,urogenital system ,COL4A3/COL4A4 MUTATIONS ,GLOMERULAR-BASEMENT-MEMBRANE ,NATURAL-HISTORY ,female genital diseases and pregnancy complications ,Nephrology ,Practice Guidelines as Topic ,FAMILIAL HEMATURIA - Abstract
Genetic testing for pathogenic COL4A3-5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3-COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.
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- 2022
23. COVID-19, Low-Molecular-Weight Heparin, and Hemodialysis
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Miriam Zacchia, Alessandra F. Perna, Mariadelina Simeoni, Francesco Trepiccione, Giovanna Capolongo, Diego Ingrosso, Perna, A., Capolongo, G., Trepiccione, F., Simeoni, M., Zacchia, M., and Ingrosso, D.
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2019-20 coronavirus outbreak ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Coronavirus disease 2019 (COVID-19) ,medicine.drug_class ,medicine.medical_treatment ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,Low molecular weight heparin ,lcsh:RC870-923 ,Betacoronavirus ,Renal Dialysi ,Renal Dialysis ,medicine ,lcsh:Dermatology ,Humans ,low-molecular-weight heparin ,Pandemics ,hemodialysis ,Pandemic ,biology ,Coronavirus Infection ,business.industry ,SARS-CoV-2 ,Anticoagulant ,Anticoagulants ,General Medicine ,Heparin ,Heparin, Low-Molecular-Weight ,lcsh:RL1-803 ,medicine.disease ,biology.organism_classification ,lcsh:Diseases of the genitourinary system. Urology ,Virology ,Pneumonia ,Editorial ,covid-19 ,Nephrology ,lcsh:RC666-701 ,Hemodialysi ,Hemodialysis ,Cardiology and Cardiovascular Medicine ,business ,Coronavirus Infections ,Human ,medicine.drug - Published
- 2020
24. MO045THE APPLICATION OF A NGS KIDNEY PANEL REVEALED KEY CHALLENGES OF PKD1-2 ANALYSIS: INTERPRETATION OF MISSENSE VARIANTS, SIGNIFICANCE OF VARIANTS IN DUPLICATED REGIONS AND HIGH ALLELIC HETEROGENEITY
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Francesca Del Vecchio Blanco, Giovambattista Capasso, Vincenzo Nigro, Giovanna Capolongo, Giancarlo Blasio, Alessandra F. Perna, and Miriam Zacchia
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Transplantation ,Kidney panel ,PKD1 ,Nephrology ,business.industry ,Pseudogene ,Key (cryptography) ,Medicine ,Missense mutation ,Allelic heterogeneity ,Computational biology ,business ,Interpretation (model theory) - Abstract
Background and Aims Genetic testing has changed the clinical management of inherited kidney diseases patients, improving prognosis, surveillance and therapy. On the other hand, it has put geneticists and clinicians in front of new challenges, as the heterogeneity of these disorders and the high number of variants, with no clear genotype-phenotype correlation. Method 108 patients underwent genetic analysis through a kidney focused NGS panel, named Nephroplex, containing 119 genetic loci associated with inherited kidney disorders. The study aimed to addressed the genetic landscape of cystic individuals and to analyze PKD1 and PKD2 variants in non-cystic individuals. Results Following diagnostic criteria, patients were divided as cystic kidney diseases (n=36) and non-cystic kidney diseases (n=72). Among the group of cystic patients, a causative mutation was detected in 51% of cases. We found thirty-seven PKD1 and PKD2 variants in 26 out of 35 individuals. In particular, 12 variants were shown to be damaging and nine of that were reported in public database, as CLINVAR and Mayo Clinic databases. Among pathogenic variants, twelve were truncating and the remaining were missense variants. Of note, 7 out of 12 damaging PKD1 mutations were located in duplicated regions. Moreover, in three cystic patients, we found a (i) a frameshift hemizygote OFD1 mutation (ii) compound heterozygote PKHD1 variants and (iii) a frameshift MUC1 variant, framing the diagnosis of oro-facio-digital type 1, autosomal recessive polycystic kidney disease and autosomal dominant tubulointerstitial disease, respectively. Interestingly, we detected 28 PKD1-2 rare variants in 21 out of 75 adult non cystic patients (28%). The most were observed in PKD1 genes (82% vs 18% in PKD2). Eighteen of 28 variants were described in the literature as likely benign or as mutations of uncertain significance, while we found 10 novel variants. In silico analysis revealed as pathogenic a frameshift mutation located in exon 15. Of note, the great part of these variations reside into the duplicated PKD1 regions. Conclusion Our data showed that genetic analysis of ADPKD retains unique challenges, given the high degree of homology of PKD1 with his pseudogenes and the high allelic heterogeneity in non-cystic individuals.
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- 2021
25. MO035COMPUTATIONAL MODELING APPROACH FOR THE COMPREHENSIVE INTERPRETATION OF RARE TUBULOPATHIES
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Miriam Zacchia, Francesco Trepiccione, Giovambattista Capasso, Valeria Columbano, Alessandra F. Perna, Davide Viggiano, Mariadelina Simeoni, Giovanna Capolongo, and Yoko Suzumoto
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Transplantation ,Bartter's syndrome ,Transmembrane domain ,Nephrology ,business.industry ,Medicine ,Computational biology ,business ,Interpretation (model theory) - Abstract
Background and Aims Kidney plays a central role on the maintenance of water homeostasis, acid-base and electrolytes balances through the activity of different types of ion channels/transporters expressed along the nephron segments. Mutations in genes encoding these transporters could subsequently lead to aberrant transporter activities, resulting in abnormal renal handling of electrolytes, thus represent monogenic form of rare kidney diseases. Accumulating number of mutations identified in genes responsible for such monogenic disorders demonstrated that eventual disease phenotypes may vary according to the type and localization of the mutation within the gene. Thus, careful evaluation of gene variation would be crucial prior to designing the strategy for the therapy in each case. Here we present various mutations from our patients, identified in genes including kcnj10, SLC12A1, SLC26A4 and clcn7 which are associated with rare tubulopathies EAST/SeSAME syndrome, Bartter’s syndrome, Pendred syndrome and Fanconi syndrome, respectively. In order to explore molecular mechanisms underlying the observed disease conditions in our patients, we have performed computational modeling analyses of these mutations in comparison with wild-type models. Method Three-dimensional homology models of Kir4.1, NKCC2, Pendrin and CLC-7 proteins were generated by Swiss-Model protein structure homology-modelling server (http://swissmodel. expasy.org) and I-TASSER server (https://zhanglab.ccmb.med.umich.edu/I-TASSER/). Disease-related mutations including novel mutations identified from our patients were mapped onto the three-dimensional models and compared with wild-type models in terms of atomic interactions as well as secondary, tertiary and quaternary structures. Furthermore, we assessed possible effects of missense mutations on the function of ion channels/transporters using online bioinformatic prediction tools PolyPhen-2, Mutation taster, PROVEAN and SIFT. Results The three-dimensional model comparison between wild-type Kir4.1 and Ala167Val variant, which is related to EAST/SeSAME syndrome, revealed that Ala167Val located at the junction between transmembrane domain 2 (TM2) and C-terminus is predicted not to interrupt the sequence of the hydrogen bonds, thus not altering the TM2 alpha-helix structure. In addition, while PolyPhen-2 and Mutation taster evaluated Ala167Val as ‘probably damaging’, PROVEAN and SIFT predicted Ala167Val as ‘neutral’ and ‘tolerated’. These observations are in line with the clinical data demonstrating the milder phenotype in patients with Ala167Val mutation compared with the ones harboring frameshift mutations leading to truncated Kir4.1 channel (Figure. 1). Furthermore, computational modeling of wild-type NKCC2 and frameshift mutation Arg302Glyfs*3 variant clearly demonstrated that Arg302Glyfs*3 results in a loss of large part of the protein, indicating that NKCC2-Arg302Glyfs*3 is practically nonfunctional (Figure. 2). Conclusion Computational modeling of disease-related mutations in various ion channels/transporters represents a novel, powerful approach for comprehensive interpretation of the disease phenotypes observed in patients with rare tubulopathies. In addition, combination of in silico modeling and clinical data could provide us with further insight into molecular mechanisms underlying the renal transporter activities. Furthermore, this in silico computational modeling approach can be applicable and suggestive for novel pharmacological intervention as well as the visual disease severity assessment.
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- 2021
26. Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria
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Tamara Nikuševa Martić, Carmela Errichiello, Albertien M. van Eerde, Anniek Corveleyn, Pascale Hilbert, Rimante Cerkauskiene, Micheel van Geel, Samuela Landini, Concetta Gangemi, Miriam Zacchia, Emma Ashton, Evelien Van Hoof, Valeria Aiello, Martin C. Gregory, Elisabeth Ars, Viviana Palazzo, Constantinos Deltas, Asheeta Gupta, Laura Massella, Susie Gear, Laith Al-Rabadi, Danica Galešić Ljubanović, Louise Hopkinson, Julia Hoefele, Jens Michael Hertz, Peter H. Byers, Elizabeth Watson, Judy Savige, Agnieszka Bierzynska, Francesca Becherucci, Pavlina Plevova, Beata S. Lipska-Ziętkiewicz, Maggie Williams, Adrian Lungu, Ania Koziell, Kathleen Claes, Agne Cerkauskaite, Francesca Mari, Hendica Belge, Alessandra Renieri, Helen Storey, Hansjorg Martin Rothe, Rachel Lennon, Savige, J., Storey, H., Watson, E., Hertz, J. M., Deltas, C., Renieri, A., Mari, F., Hilbert, P., Plevova, P., Byers, P., Cerkauskaite, A., Gregory, M., Cerkauskiene, R., Ljubanovic, D. G., Becherucci, F., Errichiello, C., Massella, L., Aiello, V., Lennon, R., Hopkinson, L., Koziell, A., Lungu, A., Rothe, H. M., Hoefele, J., Zacchia, M., Martic, T. N., Gupta, A., van Eerde, A., Gear, S., Landini, S., Palazzo, V., al-Rabadi, L., Claes, K., Corveleyn, A., Van Hoof, E., van Geel, M., Williams, M., Ashton, E., Belge, H., Ars, E., Bierzynska, A., Gangemi, C., Lipska-Zietkiewicz, B. S., RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and MUMC+: DA KG Lab Centraal Lab (9)
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Collagen Type IV ,medicine.medical_specialty ,Consensus ,IV COLLAGEN ,030232 urology & nephrology ,AMINO-ACID-SEQUENCE ,MEDICAL GENETICS ,Diseases ,Nephritis, Hereditary ,AMERICAN-COLLEGE ,Meeting Report ,urologic and male genital diseases ,Autoantigens ,DISEASE ,03 medical and health sciences ,diseases ,Alport syndrome ,0302 clinical medicine ,Genetics ,medicine ,GLYCINE SUBSTITUTIONS ,Humans ,Genetic Testing ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,business.industry ,MUTATIONS ,Molecular diagnostics ,medicine.disease ,Phenotype ,female genital diseases and pregnancy complications ,Minor allele frequency ,OSTEOGENESIS IMPERFECTA ,BASEMENT-MEMBRANE ,Practice Guidelines as Topic ,Medical genetics ,CHAIN ,business ,Nephrotic syndrome ,Minigene ,Founder effect - Abstract
The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.
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- 2021
27. Diuretic Resistance in Cardio-Nephrology: Role of Pharmacokinetics, Hypochloremia, and Kidney Remodeling
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Mariadelina Simeoni, Miriam Zacchia, Davide Viggiano, Pietro Anastasio, Ida Molfino, Cristina Masella, Giovanna Capolongo, Masella, C., Viggiano, D., Molfino, I., Zacchia, M., Capolongo, G., Anastasio, P., and Simeoni, M.
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Nephrology ,Drug ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,medicine.medical_treatment ,media_common.quotation_subject ,Hypochloremia ,030232 urology & nephrology ,Heart failure ,Kidney ,lcsh:RC870-923 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,lcsh:Dermatology ,medicine ,Humans ,Diuretic ,Diuretics ,Intensive care medicine ,Vaptans ,media_common ,Cardio-Renal Syndrome ,Renal sodium reabsorption ,business.industry ,Vaptan ,General Medicine ,lcsh:RL1-803 ,Diuretic resistance ,Fluid overload ,lcsh:Diseases of the genitourinary system. Urology ,medicine.disease ,medicine.anatomical_structure ,lcsh:RC666-701 ,Cardiology and Cardiovascular Medicine ,Hyponatremia ,business ,Human - Abstract
Background: Diuretic resistance is among the most challenging problems that the cardio-nephrologist must address in daily clinical practice, with a considerable burden on hospital admissions and health care costs. Indeed, loop diuretics are the first-line therapy to overcome fluid overload in heart failure patients. The pathophysiological mechanisms of fluid and sodium retention are complex and depend on several neuro-hormonal signals mainly acting on sodium reabsorption along the renal tubule. Consequently, doses and administration modalities of diuretics must be carefully tailored to patients in order to overcome under- or overtreatment. The frequent and tricky development of diuretic resistance depends in part on post-diuretic sodium retention, reduced tubular secretion of the drug, and reduced sodium/chloride sensing. Sodium and chloride depletions have been recently shown to be major factors mediating these processes. Aquaretics and high-saline infusions have been recently suggested in cases of hyponatremic conditions. This review discusses the limitations and strengths of these approaches. Summary: Long-term diuretic use may lead to diuretic resistance in cardio-renal syndromes. To overcome this complication intravenous administration of loop diuretics and a combination of different diuretic classes have been proposed. In the presence of hyponatremia, high-saline solutions in addition to loop diuretics might be beneficial, whereas aquaretics require caution to avoid overcorrection. Key Messages: Diuretic resistance is a central theme for cardio-renal syndromes. Hyponatremia and hypochloremia may be part of the mechanisms for diuretic resistance. Aquaretics and high-saline solutions have been proposed as possible new therapeutic solutions.
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- 2019
28. Urine concentrating defect as presenting sign of progressive renal failure in Bardet-Biedl syndrome patients
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Giancarlo Blasio, Francesco Trepiccione, Raffaele Raucci, Perna Alessandra, Vincenzo Nigro, Francesca Simonelli, Maria Elena Onore, Giovambattista Capasso, Valentina Di Iorio, Miriam Zacchia, Davide Viggiano, Emanuela Marchese, Caterina Vitagliano, Annalaura Torella, Francesca Del Vecchio Blanco, Zacchia, Miriam, Blanco, Francesca Del Vecchio, Torella, Annalaura, Raucci, Raffaele, Blasio, Giancarlo, Onore, Maria Elena, Marchese, Emanuela, Trepiccione, Francesco, Vitagliano, Caterina, Iorio, Valentina Di, Perna, Alessandra, Simonelli, Francesca, Nigro, Vincenzo, Capasso, Giovambattista, and Viggiano, Davide
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medicine.medical_specialty ,kidney disease ,030232 urology & nephrology ,Urology ,Renal function ,GFR ,Excretion ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,genetics ,AcademicSubjects/MED00340 ,030304 developmental biology ,0303 health sciences ,Transplantation ,Kidney ,Creatinine ,business.industry ,urine osmolality ,Furosemide ,Original Articles ,medicine.disease ,medicine.anatomical_structure ,ciliopathy ,chemistry ,Nephrology ,Urine osmolality ,genetic ,business ,Hyposthenuria ,Kidney disease ,medicine.drug - Abstract
BackgroundUrine concentrating defect is a common dysfunction in ciliopathies, even though its underlying mechanism and its prognostic meaning are largely unknown. This study assesses renal function in a cohort of 54 Bardet–Biedl syndrome (BBS) individuals and analyses whether renal hyposthenuria is the result of specific tubule dysfunction and predicts renal disease progression.MethodsThe estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (ACR) and maximum urine osmolality (max-Uosm) were measured in all patients. Genetic analysis was conducted in 43 patients. Annual eGFR decline (ΔeGFR) was measured in patients with a median follow-up period of 6.5 years. Urine aquaporin-2 (uAQP2) excretion was measured and the furosemide test was performed in patients and controls.ResultsAt baseline, 33 (61.1%), 12 (22.2%) and 9 (16.7%) patients showed an eGFR >90, 60–90 and 30 mg/g and 55.8% of patients showed urine concentrating defect in the absence of renal insufficiency. Baseline eGFR, but not max-Uosm, correlated negatively with age. Conversely, truncating mutations affected max-Uosm and showed a trend towards a reduction in eGFR. Max-Uosm correlated with ΔeGFR (P ConclusionsHyposthenuria is a warning sign predicting poor renal outcome in BBS. The pathophysiology of this defect is most likely beyond defective tubular function.
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- 2021
29. Diffusion tensor imaging for the study of early renal dysfunction in patients affected by bardet-biedl syndrome
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Marco Salvatore, Carlo Cavaliere, Pasquale Borrelli, Miriam Zacchia, Marco Aiello, Giovambattista Capasso, Luca Basso, Borrelli, P., Zacchia, M., Cavaliere, C., Basso, L., Salvatore, M., Capasso, G., and Aiello, M.
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Adult ,Male ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Medullary cavity ,Renal cortex ,Science ,Urology ,Renal function ,Kidney ,Article ,Young Adult ,Bardet–Biedl syndrome ,Chronic kidney disease ,Fractional anisotropy ,Medicine ,Humans ,Renal Insufficiency, Chronic ,Bardet-Biedl Syndrome ,Multidisciplinary ,business.industry ,medicine.disease ,medicine.anatomical_structure ,Diffusion Tensor Imaging ,Female ,business ,Body mass index ,Diffusion MRI ,Glomerular Filtration Rate - Abstract
Kidney structural abnormalities are common features of Bardet-Biedl syndrome (BBS) patients that lead to a progressive decline in renal function. Magnetic resonance diffusion tensor imaging (DTI) provides useful information on renal microstructures but it has not been applied to these patients. This study investigated using DTI to detect renal abnormalities in BBS patients with no overt renal dysfunction. Ten BBS subjects with estimated glomerular filtration rates over 60 ml/min/1.73m2 and 14 individuals matched for age, gender, body mass index and renal function were subjected to high-field DTI. Fractional anisotropy (FA), and mean, radial and axial diffusivity were evaluated from renal cortex and medulla. Moreover, the corticomedullary differentiation of each DTI parameter was compared between groups. Only cortical FA statistically differed between BBS patients and controls (p = 0.033), but all the medullary DTI parameters discriminated between the two groups with lower FA (p
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- 2021
30. [Application of proteomics and metabolomics to study inherited kidney disorders: from big data to precision medicine]
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Angela, Cervesato, Raffaele, Raucci, Dario, Buononato, Emanuela, Marchese, Giovanna, Capolongo, Alessandra, Perna, Giovambattista, Capasso, and Miriam, Zacchia
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Big Data ,Proteomics ,Mice ,Polycystic Kidney Diseases ,Animals ,Humans ,Metabolomics ,Precision Medicine ,Biomarkers ,Rats - Abstract
The recent application of proteomics and metabolomics to clinical medicine has demonstrated their potential role in complementing genomics for a better understanding of diseases' patho-physiology. These technologies offer the clear opportunity to identify risk factors, disease-specific or stage-specific biomarkers and to predict therapeutic response. This article is an overview of the recent insights obtained by metabolomic and proteomic studies in inherited kidney disorders. Proteomics studies have allowed the definition of a detailed picture of protein composition, post-translational modifications and interactions in kidney-derived samples, improving our understanding of renal physiology, especially of tubular transport and primary cilium-related functions. Studies on patients' urine samples and experimental models of inherited kidney diseases have provided clues suggesting novel potential pathological mechanisms and biomarkers of disease, for example in polycystic kidney disease. Metabolomic-based studies have been recently applied to assess biological system disturbances caused by specific genetic mutations resulting in inherited kidney disorders. These studies have been mainly carried out on mouse and rat models of cystic and metabolic disorders (such as Fabry disease), and on patients' urine samples. They have provided a significant contribution in understanding disease pathophysiology, promoting the discovery of aberrant biochemical pathways and contributing to the development of targeted therapies.
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- 2020
31. P0031AURINE METABOLOMICS: AN EMERGING TOOL FOR DISSECTING BIOLOGICAL ABERRATIONS UNDERLYING RENAL DYSFUNCTION IN BARDET-BIEDL SYNDROME
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Giovambattista Capasso, Marianna Caterino, Emanuela Marchese, Margherita Ruoppolo, and Miriam Zacchia
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Transplantation ,Metabolomics ,Bardet–Biedl syndrome ,Nephrology ,business.industry ,Genetic disorder ,medicine ,medicine.disease ,Bioinformatics ,business ,Ciliopathies - Abstract
Background and Aims Bardet Biedl Syndrome (BBS) is a rare genetic disorder characterized by a wide range of organ dysfunction, including kidney disease. The severity of renal dysfunction is highly variable in this setting, ranging from tubular defects to the end stage renal disease, with poor genotype-phenotype correlation. Proteomics and metabolomics are powerful tools able to contribute to the better understanding of molecular basis of disease conditions. Our previous studies demonstrated that the urinary proteomic pattern of BBS patients differed from that of healthy subjects, with a set of deregulated proteins including cell adhesion and extracellular matrix organization proteins (1). The present study aims to characterize urine metabolomic profile of BBS patients, in order to identify both 1) potential disease biomarkers and 2) aberrant metabolic pathways underlying renal disease Method To this end, in the pilot study urine samples have been collected from 14 adult BBS patients and have been compared with healthy volunteers, using an untargeted strategy. In the confirmation study, 24 BBS patients with wide range of kidney dysfunction have been enrolled, and additional control groups, besides healthy subjects, were included: 1) age-gender-matched chronic kidney disease patients by other causes and 2) obese individuals. Results Several metabolites were de-regulated in BBS patients compared with normal subjects (lactic acid, glycolic acid,3-Hydroxypropionic acid, pyruvic acid, 3-hydroxyisobutyric acid, 2-ethyl-3-hydroxy-propionic acid, succinic acid, fumaric acid, erythropentonic acid, 2-hydroxyglutaric acid, 4-hydroxyphenyllactic acid, 3,4-pyridinedicarboxylic acid, retinoic acid, 4-hydroxyphenylacetic acid, palmitic acid, 9-Hexadecenoic acid, oleic acid and 9-Octadecenoic acid). The clusterization performed by MetaboAnalyst tool, revealed a possible deregulation of different metabolic pathways, including glycolysis, TCA cycle, pyruvate metabolism, lipids biosynthesis and glutamate metabolism (p-value Conclusion These findings suggest that urine metabolomic fingerprint of BBS patients is different from that of healthy subjects and indicate a possible deregulation of several metabolic pathways; some urinary molecules correlated with kidney dysfunction only in BBS patients, suggesting the specificity of these results.
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- 2020
32. Characterization of five novel vasopressin V2 receptor mutants causing nephrogenic diabetes insipidus reveals a role of tolvaptan for M272R-V2R mutation
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Emanuele Miraglia del Giudice, Pierluigi Marzuillo, Stefano Guarino, Vincenzo Costanzo, Anna Iervolino, Emmanuelle Cordat, Giovambattista Capasso, Miriam Zacchia, Yoko Suzumoto, Francesco Trepiccione, Federica Prosperi, Alessandra F. Perna, Angela La Manna, Sabina Jelen, Prosperi, Federica, Suzumoto, Yoko, Marzuillo, Pierluigi, Costanzo, Vincenzo, Jelen, Sabina, Iervolino, Anna, Guarino, Stefano, La Manna, Angela, Miraglia Del Giudice, Emanuele, Perna, Alessandra F, Zacchia, Miriam, Cordat, Emmanuelle, Capasso, Giovambattista, and Trepiccione, Francesco
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Vasopressin ,Receptors, Vasopressin ,Glycosylation ,Vasopressins ,Mutant ,030232 urology & nephrology ,Tolvaptan ,lcsh:Medicine ,Diabetes Insipidus, Nephrogenic ,medicine.disease_cause ,Endoplasmic Reticulum ,Article ,Cell Line ,Madin Darby Canine Kidney Cells ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Dogs ,Tubulopathy ,Internal medicine ,Arginine vasopressin receptor 2 ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,lcsh:Science ,Mutation ,Multidisciplinary ,Chemistry ,lcsh:R ,Cell Membrane ,Nephrons ,medicine.disease ,Nephrogenic diabetes insipidus ,Protein Transport ,030104 developmental biology ,Endocrinology ,COS Cells ,lcsh:Q ,Acid, base, fluid, electrolyte disorders ,Antidiuretic Hormone Receptor Antagonists ,medicine.drug - Abstract
Nephrogenic diabetes insipidus (NDI) is a rare tubulopathy characterized by urinary concentration defect due to renal resistance to vasopressin. Loss-of-function mutations of vasopressin V2 receptor (V2R) gene (AVPR2) is the most common cause of the disease. We have identified five novel mutations L86P, R113Q, C192S, M272R, and W323_I324insR from NDI-affected patients. Functional characterization of these mutants revealed that R113Q and C192S were normally localized at the basolateral membrane of polarized Madin-Darby Canine Kidney (MDCK) cells and presented proper glycosylation maturation. On the other side, L86P, M272R, and W323_I324insR mutants were retained in endoplasmic reticulum and exhibited immature glycosylation and considerably reduced stability. All five mutants were resistant to administration of vasopressin analogues as evaluated by defective response in cAMP release. In order to rescue the function of the mutated V2R, we tested VX-809, sildenafil citrate, ibuprofen and tolvaptan in MDCK cells. Among these, tolvaptan was effective in rescuing the function of M272R mutation, by both allowing proper glycosylation maturation, membrane sorting and response to dDAVP. These results show an important proof of concept for the use of tolvaptan in patients affected by M272R mutation of V2R causing NDI.
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- 2020
33. Looking beyond Entecavir to discover Gitelman Syndrome in a 50 year-old man
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Miriam Zacchia, L Salviano, Alessandra F. Perna, Mariadelina Simeoni, Giovambattista Capasso, F. Del Vecchio Blanco, Francesco Trepiccione, Y Suzumoto, Vincenzo Nigro, V Columbano, Giovanna Capolongo, Simeoni, Mariadelina, Columbano, Valeria, Suzumoto, Yoko, Salviano, Luca, Capolongo, Giovanna, Zacchia, Miriam, Del Vecchio Blanco, Francesca, Perna, Alessandra, Nigro, Vincenzo, Capasso, Giovambattista, and Trepiccione, Francesco
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Male ,Pediatrics ,medicine.medical_specialty ,NCC ,Guanine ,business.industry ,General Medicine ,Entecavir ,Middle Aged ,Gitelman syndrome ,medicine.disease ,metabolic alkalosis ,direct acting antiviral ,medicine ,hypokalemia ,Humans ,SLC12A3 ,business ,medicine.drug ,entecavir - Abstract
Potassium (K+) is essential for cells functions and alterations of the normal plasmatic levels can be life-threatening. The kidney is crucial in maintaining K+ homeostasis, mainly by regulating its secretion in the urine. Hypokalemia is influenced by acid-base status and can be associated to both metabolic alkalosis or acidosis. In adults, drug-induced hypokalemia is the most common form, however, genetically undiagnosed conditions should always be investigated.
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- 2020
34. Urine concentrating defect as presenting sign of progressive re- nal failure in BBS patients
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Miriam, Zacchia, Francesca Del Vecchio Blanco, Annalaura, Torella, Raffaele, Raucci, Giancarlo, Blasio, Maria Elena Onore, Emanuela, Marchese, Francesco, Trepiccione, Caterina, Vitagliano, Valentina Di Iorio, Perna, Alessandra, Francesca, Simonelli, Vincenzo, Nigro, Giovambattista, Capasso, and Viggiano, Davide
- Published
- 2020
35. Exploring Key Challenges of Understanding the Pathogenesis of Kidney Disease in Bardet–Biedl Syndrome
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Margherita Ruoppolo, Miriam Zacchia, Emanuela Marchese, Giovambattista Capasso, Alessandra F. Perna, Marchese, E., Ruoppolo, M., Perna, A., Capasso, G., Zacchia, M., Marchese, E, Ruoppolo, M, Perna, A, and Capasso, G
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BBS2 ,BBS1 ,ciliopathie ,kidney disease ,030232 urology & nephrology ,BBS10 ,Kidney development ,Review ,030204 cardiovascular system & hematology ,Bioinformatics ,lcsh:RC870-923 ,03 medical and health sciences ,0302 clinical medicine ,Bardet–Biedl syndrome ,medicine ,genetics ,business.industry ,medicine.disease ,lcsh:Diseases of the genitourinary system. Urology ,Penetrance ,Ciliopathy ,Nephrology ,ciliopathies ,genetic ,physiopathology ,business ,Kidney disease - Abstract
Bardet–Biedl syndrome (BBS) is a rare pleiotropic inherited disorder known as a ciliopathy. Kidney disease is a cardinal clinical feature; however, it is one of the less investigated traits. This study is a comprehensive analysis of the literature aiming to collect available information providing mechanistic insights into the pathogenesis of kidney disease by analyzing clinical and basic science studies focused on this issue. The analysis revealed that the syndrome is either clinically and genetically heterogenous, with 24 genes discovered to date, but with 3 genes (BBS1, BBS2, and BBS10) accounting for almost 50% of diagnoses; genotype–phenotype correlation studies showed that patients with BBS1 mutations have a less severe renal phenotype than the other 2 most common loci; in addition, truncating rather than missense mutations are more likely to cause kidney disease. However, significant intrafamilial clinical variability has been described, with no clear explanation to date. In mice kidneys, Bbs genes have relative low expression levels, in contrast with other common affected organs, like the retina; surprisingly, Bbs1 is the only locus with basal overexpression in the kidney. In vitro studies indicate that signalling pathways involved in embryonic kidney development and repair are affected in the context of BBS depletion; in mice, kidney disease does not have a full penetrance; when present, it resembles human phenotype and shows an age-dependent progression. Data on the exact contribution of local versus systemic consequences of Bbs dysfunction are scanty and further investigations are required to get firm conclusions.
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- 2020
36. Proteomics and metabolomics studies exploring the pathophysiology of renal dysfunction in autosomal dominant polycystic kidney disease and other ciliopathies
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Margherita Ruoppolo, Giovambattista Capasso, Miriam Zacchia, Marianna Caterino, Emanuela Marchese, Elena Martina Trani, Alessandra F. Perna, Giovanna Capolongo, Zacchia, Miriam, Marchese, Emanuela, Martina Trani, Elena, Caterino, Marianna, Capolongo, Giovanna, Perna, Alessandra, Ruoppolo, Margherita, Capasso, Giovambattista, Zacchia, M., Marchese, E., Trani, E. M., Caterino, M., Capolongo, G., Perna, A., Ruoppolo, M., and Capasso, G.
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0301 basic medicine ,Proteome ,030232 urology & nephrology ,Autosomal dominant polycystic kidney disease ,Metabolomic ,Disease ,Bioinformatics ,Proteomics ,Kidney ,Ciliopathies ,Ciliopathie ,03 medical and health sciences ,proteomics ,0302 clinical medicine ,Metabolomics ,renal disease ,ciliopathies, metabolomics, primary cilium, prote- omics,renaldisease ,medicine ,Animals ,Humans ,Transplantation ,business.industry ,Cilium ,Proteomic ,medicine.disease ,Polycystic Kidney, Autosomal Dominant ,metabolomics ,030104 developmental biology ,medicine.anatomical_structure ,Nephrology ,Metabolome ,business ,primary cilium ,Kidney disease ,Signal Transduction - Abstract
The primary cilium (PC) was considered as a vestigial organelle with no significant physiological importance, until the discovery that PC perturbation disturbs several signalling pathways and results in the dysfunction of a variety of organs. Genetic studies have demonstrated that mutations affecting PC proteins or its anchoring structure, the basal body, underlie a class of human disorders (known as ciliopathies) characterized by a constellation of clinical signs. Further investigations have demonstrated that the PC is involved in a broad range of biological processes, in both developing and mature tissues. Kidney disease is a common clinical feature of cilia disorders, supporting the hypothesis of a crucial role of the PC in kidney homoeostasis. Clinical proteomics and metabolomics are an expanding research area. Interestingly, the application of these methodologies to the analysis of urine, a biological sample that can be collected in a non-invasive fashion and possibly in large amounts, makes these studies feasible also in patients. The present article describes the most recent proteomic and metabolomic studies exploring kidney dysfunction in the setting of ciliopathies, showing the potential of these methodologies in the elucidation of disease pathophysiology and in the discovery of biomarkers.
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- 2020
37. Urinary metabolic profile of patients with transfusion-dependent β-thalassemia major undergoing deferasirox therapy
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Aldo Filosa, Amerigo Beneduci, Giuseppina De Luca, Giovanna Capolongo, Patrizia Cinque, Miriam Zacchia, Giovambattista Capasso, Francesco Trepiccione, Silvia Costantini, Anna Spasiano, Maria Enrica Di Pietro, Paolo Ricchi, Capolongo, G., Zacchia, M., Beneduci, A., Costantini, S., Cinque, P., Spasiano, A., De Luca, G., Di Pietro, M. E., Ricchi, P., Trepiccione, F., Capasso, G., and Filosa, A.
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Adult ,Male ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,Metabolite ,Urinary system ,030232 urology & nephrology ,Renal function ,Metabolomic ,Urinomic ,Urine ,Urinalysis ,lcsh:RC870-923 ,urologic and male genital diseases ,Gastroenterology ,Renal disease ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Urinomics ,Internal medicine ,Tubular function ,lcsh:Dermatology ,medicine ,Metabolomics ,Humans ,Hypercalciuria ,Kidney ,business.industry ,Deferasirox ,beta-Thalassemia ,General Medicine ,lcsh:RL1-803 ,lcsh:Diseases of the genitourinary system. Urology ,medicine.disease ,medicine.anatomical_structure ,chemistry ,lcsh:RC666-701 ,Nephrology ,β-Thalassemia major ,Female ,Cardiology and Cardiovascular Medicine ,Complication ,business ,medicine.drug - Abstract
Introduction: Renal dysfunction is a frequent complication in patients suffering from β-thalassemia major (β-TM). The aim of this study was to analyze the renal function and urine metabolomic profile of β-TM patients undergoing transfusions and deferasirox (DFX) therapy, in order to better characterize and shed light on the pathogenesis of renal disease in this setting. Methods and Subjects: 40 patients affected by β-TM treated with DFX and 35 age- and gender-matched healthy controls were enrolled in the study. Renal function was assessed. Glomerular filtration rate (GFR) was estimated with CKD-EPI and Schwartz formula for adults and children, respectively. Renal tubular function and maximal urine concentration ability were tested. Urine specimens were analyzed by nuclear magnetic resonance spectroscopy to identify the urinary metabolite profiles. Results: The study of renal function in β-TM patients revealed normal estimated (e)GFR mean values and the albumin-to-creatinine ratio was Discussion: The major finding of this work is that β-TM patients and controls exhibit different concentrations of some metabolites in the urine. Early recognition of urinary abnormalities may be useful to detect and prevent kidney damage.
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- 2020
38. Urine Proteomics Revealed a Significant Correlation Between Urine-Fibronectin Abundance and Estimated-GFR Decline in Patients with Bardet-Biedl Syndrome
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Giuliana Bruno, Giovambattista Capasso, Maria Fiorella Mazzeo, Margherita Ruoppolo, Rosa Anna Siciliano, Davide Arcaniolo, Francesco Trepiccione, Miriam Zacchia, Marianna Caterino, Michele Costanzo, Caterino, M, Zacchia, M, Costanzo, Michele, Bruno, G, Arcaniolo, D, Trepiccione, F, Siciliano, Ra, Mazzeo, MARIA FIORELLA, Ruoppolo, M, Capasso, G, Caterino, Marianna, Zacchia, Miriam, Bruno, Giuliana, Arcaniolo, Davide, Trepiccione, Francesco, Anna Siciliano, Rosa, Fiorella Mazzeo, Maria, Ruoppolo, Margherita, and Capasso, Giovambattista
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Adult ,Male ,Proteomics ,0301 basic medicine ,lcsh:Diseases of the circulatory (Cardiovascular) system ,·Urine proteome ,medicine.medical_specialty ,Proteome ,Urinary system ,030232 urology & nephrology ,Renal function ,Urine ,lcsh:RC870-923 ,Gastroenterology ,Pathogenesis ,Young Adult ,Urine proteome ,03 medical and health sciences ,0302 clinical medicine ,Bardet–Biedl syndrome ,Fibrosis ,Internal medicine ,lcsh:Dermatology ,medicine ,Renal fibrosis ,Humans ,Kidney dysfunction ,Fibronectin ,business.industry ,General Medicine ,lcsh:RL1-803 ,Middle Aged ,lcsh:Diseases of the genitourinary system. Urology ,medicine.disease ,Fibronectins ,030104 developmental biology ,lcsh:RC666-701 ,Nephrology ,Case-Control Studies ,GFR decline ,Female ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Bardet-biedl syndrome ,Glomerular Filtration Rate ,Extracellular matrix organization - Abstract
Background:/Aims: Renal disease is a common cause of morbidity in patients with Bardet-Biedl syndrome (BBS), however the severity of kidney dysfunction is highly variable. To date, there is little information on the pathogenesis, the risk and predictor factors for poor renal outcome in this setting. The present study aims to analyze the spectrum of urinary proteins in BBS patients, in order to potentially identify 1) disease-specific proteomic profiles that may differentiate the patients from normal subjects; 2) urinary markers of renal dysfunction. Methods: Fourteen individuals (7 males and 7 females) with a clinical diagnosis of BBS have been selected in this study. A pool of 10 aged-matched males and 10 aged-matched females have been used as controls for proteomic analysis. The glomerular filtration rate (eGFR) has been estimated using the CKD-EPI formula. Variability of eGFR has been retrospectively assessed calculating average annual eGFR decline (ΔeGFR) in a mean follow-up period of 4 years (3-7). Results: 42 proteins were significantly over- or under-represented in BBS patients compared with controls; the majority of these proteins are involved in fibrosis, cell adhesion and extracellular matrix organization. Statistic studies revealed a significant correlation between urine fibronectin (u-FN) (r2=0.28; p2 =0.35; p20.27; p2 =0.2389; pConclusion: The present study demonstrates that urine proteome of BBS patients differs from that of normal subjects; in addition, kidney dysfunction correlated with urine abundance of known markers of renal fibrosis.
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- 2018
39. Impact of Local and Systemic Factors on Kidney Dysfunction in Bardet-Biedl Syndrome
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Vincent Marion, Francesco Trepiccione, Miriam Zacchia, Giovanna Capolongo, Zacchia, Miriam, Capolongo, Giovanna, Trepiccione, Francesco, and Marion, Vincent
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congenital, hereditary, and neonatal diseases and abnormalities ,lcsh:Diseases of the circulatory (Cardiovascular) system ,030232 urology & nephrology ,Renal function ,Disease ,030204 cardiovascular system & hematology ,Bioinformatics ,lcsh:RC870-923 ,Ciliopathies ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Bardet–Biedl syndrome ,lcsh:Dermatology ,Medicine ,Humans ,Cilia ,Renal Insufficiency ,Bardet-Biedl Syndrome ,Bardet-Biedl ,Kidney Defects ,business.industry ,Mechanism (biology) ,Cilium ,Kidney dysfunction ,General Medicine ,Primary Cilium ,lcsh:RL1-803 ,medicine.disease ,Kidney Defect ,lcsh:Diseases of the genitourinary system. Urology ,Nephrology ,lcsh:RC666-701 ,Cardiology and Cardiovascular Medicine ,business - Abstract
Bardet Biedl syndrome (BBS) is a rare inherited syndromic condition characterized by renal and extra-renal disorders. Renal defect, at either structural or functional level, is one of the cardinal clinical features, and is a major cause of morbidity. However, the pathogenic mechanism underlying its dysfunction remains largely unknown, and to date only symptomatic treatment with no specific therapy is available for these patients. Elucidating aberrant cellular and/or systemic processes that impact kidney function is therefore a prerequisite to develop targeted innovative therapeutic strategies for the BBS patients. Given the proven role of BBS proteins in the function of the primary cilium (PC) and considering the clinical overlapping of BBS with other ciliopathies, BBS is considered the result of disruption of ciliary activities. The present review aims at giving an updated overview of the spectrum of renal abnormalities in BBS patients according to the existing scientific literature, and discusses the possible role of intrinsic PC dysfunction into the pathogenesis of renal defects based on the most recent findings demonstrating a possible role of systemic factors in favoring the progression of renal disease. (c) 2017 The Author(s) Published by S. Karger AG, Basel
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- 2017
40. Integration of Proteomics and Metabolomics in Exploring Genetic and Rare Metabolic Diseases
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Giuliana Bruno, Margherita Ruoppolo, Daniela Crisci, Miriam Zacchia, Marianna Caterino, Michele Costanzo, Costanzo, Michele, Zacchia, Miriam, Bruno, Giuliana, Crisci, Daniela, Caterino, Marianna, and Ruoppolo, Margherita
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Proteomics ,0301 basic medicine ,business.industry ,Catabolism ,The Kidney in Genetic and Rare Diseases: Review ,010401 analytical chemistry ,Metabolomic ,Biomarker ,Inborn errors of metabolism ,Metabolism ,Computational biology ,Omics ,01 natural sciences ,0104 chemical sciences ,Transplantation ,Acylcarnitine ,03 medical and health sciences ,030104 developmental biology ,Metabolomics ,Biochemistry ,Urea cycle ,Medicine ,Identification (biology) ,business - Abstract
Background: Inherited metabolic disorders or inborn errors of metabolism are caused by deficiency of enzymatic activities in the catabolism of amino acids, carbohydrates, or lipids. These disorders include aminoacidopathies, urea cycle defects, organic acidemias, defects of oxidation of fatty acids, and lysosomal storage diseases. Inborn errors of metabolism constitute a significant proportion of genetic diseases, particularly in children; however, they are individually rare. Clinical phenotypes are very variable, some of them remain asymptomatic, others manifest metabolic decompensation in neonatal age, and others encompass mental retardation at later age. The clinical manifestation of these disorders can involve different organs and/or systems. Some disorders are easily managed if promptly diagnosed and treated, whereas in other cases neither diet, vitamin therapy, nor transplantation appears to prevent multi-organ impairment. Summary: Here, we discuss the principal challenges of metabolomics and proteomics in inherited metabolic disorders. We review the recent developments in mass spectrometry-based proteomic and metabolomic strategies. Mass spectrometry has become the most widely used platform in proteomics and metabolomics because of its ability to analyze a wide range of molecules, its optimal dynamic range, and great sensitivity. The fast measurement of a broad spectrum of metabolites in various body fluids, also collected in small samples like dried blood spots, have been facilitated by the use of mass spectrometry-based techniques. These approaches have enabled the timely diagnosis of inherited metabolic disorders, thereby facilitating early therapeutic intervention. Due to its analytical features, proteomics is suited for the basic investigation of inborn errors of metabolism. Modern approaches enable detailed functional characterization of the pathogenic biochemical processes, as achieved by quantification of proteins and identification of their regulatory chemical modifications. Key Message: Mass spectrometry-based “omics” approaches most frequently used to study the molecular mechanisms underlying inherited metabolic disorders pathophysiology are described.
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- 2017
41. A fate-mapping approach reveals the composite origin of the connecting tubule and alerts on 'single-cell'-specific KO model of the distal nephron
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Anna Iervolino, Federica Petrillo, Günther Schütz, Juliette Hadchouel, Francesco Trepiccione, Giovambattista Capasso, Christelle Soukaseum, Dominique Eladari, Miriam Zacchia, Trepiccione, Francesco, Soukaseum, Christelle, Iervolino, Anna, Petrillo, Federica, Zacchia, Miriam, Schütz, Gunther, Eladari, Dominique, Capasso, Giovambattista, and Hadchouel, Juliette
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0301 basic medicine ,Cell type ,Physiology ,Mice, Transgenic ,Nephron ,Biology ,Models, Biological ,Distal nephron ,Mice ,03 medical and health sciences ,Fate mapping ,medicine ,Animals ,Connecting tubule ,Kidney Tubules, Collecting ,Kidney Tubules, Distal ,NCC ,Aquaporin 2 ,urogenital system ,Nephrons ,Anatomy ,AQP2 ,Sodium Chloride Symporters ,Epithelium ,030104 developmental biology ,medicine.anatomical_structure ,Duct (anatomy) - Abstract
The distal nephron is a heterogeneous part of the nephron composed by six different cell types, forming the epithelium of the distal convoluted (DCT), connecting, and collecting duct. To dissect the function of these cells, knockout models specific for their unique cell marker have been created. However, since this part of the nephron develops at the border between the ureteric bud and the metanephric mesenchyme, the specificity of the single cell markers has been recently questioned. Here, by mapping the fate of the aquaporin 2 (AQP2) and Na+-Cl−cotransporter (NCC)-positive cells using transgenic mouse lines expressing the yellow fluorescent protein fluorescent marker, we showed that the origin of the distal nephron is extremely composite. Indeed, AQP2-expressing precursor results give rise not only to the principal cells, but also to some of the A- and B-type intercalated cells and even to cells of the DCT. On the other hand, some principal cells and B-type intercalated cells can develop from NCC-expressing precursors. In conclusion, these results demonstrate that the origin of different cell types in the distal nephron is not as clearly defined as originally thought. Importantly, they highlight the fact that knocking out a gene encoding for a selective functional marker in the adult does not guarantee cell specificity during the overall kidney development. Tools allowing not only cell-specific but also time-controlled recombination will be useful in this sense.
- Published
- 2016
42. Lanthionine and Other Relevant Sulfur Amino Acid Metabolites: Detection of Prospective Uremic Toxins in Serum by Multiple Reaction Monitoring Tandem Mass Spectrometry
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Alessandra F, Perna, Francesca, Pane, Nunzio, Sepe, Carolina, Fontanarosa, Gabriella, Pinto, Miriam, Zacchia, Francesco, Trepiccione, Evgeniya, Anishchenko, Diego, Ingrosso, Piero, Pucci, and Angela, Amoresano
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Male ,Amino Acids, Sulfur ,Alanine ,Renal Dialysis ,Tandem Mass Spectrometry ,Humans ,Hydrogen Sulfide ,Renal Insufficiency, Chronic ,Sulfides ,Chromatography, Liquid - Abstract
In the context of the vascular effects of hydrogen sulfide (H
- Published
- 2019
43. Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium
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Luigi Mele, Alessandra F. Perna, Carmela Vigorito, Diego Ingrosso, Rosanna Capasso, Patrizia Lombari, Giovanna Capolongo, Francesco Trepiccione, Evgeniya Anishchenko, Miriam Zacchia, Vigorito, Carmela, Anishchenko, Evgeniya, Mele, Luigi, Capolongo, Giovanna, Trepiccione, Francesco, Zacchia, Miriam, Lombari, Patrizia, Capasso, Rosanna, Ingrosso, Diego, and Perna, Alessandra
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Vascular Endothelial Growth Factor A ,sulfane sulfur ,uremic toxin ,Transsulfuration ,Transsulfuration pathway ,Calcium in biology ,lcsh:Chemistry ,H2S ,chemistry.chemical_compound ,Hydrogen Sulfide ,glutathione ,lcsh:QH301-705.5 ,Spectroscopy ,chemistry.chemical_classification ,Alanine ,calcium homeostasis ,Calcium homeostasi ,General Medicine ,Flow Cytometry ,Computer Science Applications ,Amino acid ,Amino Acids, Sulfur ,Vascular endothelial growth factor A ,Biochemistry ,Oxidation-Reduction ,VEGFA ,lanthionine ,Cystathionine beta-Synthase ,Neovascularization, Physiologic ,CSE ,Sulfides ,Article ,Catalysis ,Cell Line ,CBS ,Inorganic Chemistry ,Humans ,Renal Insufficiency, Chronic ,Physical and Theoretical Chemistry ,Molecular Biology ,Lanthionine ,Uremia ,Calcium metabolism ,Organic Chemistry ,Endothelial Cells ,Glutathione ,equipment and supplies ,MicroRNAs ,lcsh:Biology (General) ,lcsh:QD1-999 ,Gene Expression Regulation ,chemistry ,Calcium ,chronic kidney disease - Abstract
(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release, reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-&beta, synthase, modifies the expression of miR-200c and miR-423, lowers expression of vascular endothelial growth factor VEGF, increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.
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- 2019
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44. Lanthionine and Other Relevant Sulfur Amino Acid Metabolites: Detection of Prospective Uremic Toxins in Serum by Multiple Reaction Monitoring Tandem Mass Spectrometry
- Author
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Francesco Trepiccione, Gabriella Pinto, Carolina Fontanarosa, Miriam Zacchia, Alessandra F. Perna, Francesca Pane, Evgeniya Anishchenko, Diego Ingrosso, Angela Amoresano, Piero Pucci, Nunzio Sepe, Bełtowski J., Perna, Alessandra F., Pane, Francesca, Sepe, Nunzio, Fontanarosa, Carolina, Pinto, Gabriella, Zacchia, Miriam, Trepiccione, Francesco, Anishchenko, Evgeniya, Ingrosso, Diego, Pucci, Pietro, Amoresano, Angela, Perna AF, Pane F, Sepe N, Fontanarosa C, Pinto G, Zacchia M, Trepiccione F, Anishchenko E, Ingrosso D, Pucci P, Amoresano A, Bełtowski J, Perna, Af, Pane, F, Sepe, N, Fontanarosa, C, Pinto, G, Trepiccione, F, Anishchenko, E, Ingrosso, D, Pucci, P, and Amoresano, A.
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Multiple reaction monitoring ,0301 basic medicine ,Metabolomic ,Context (language use) ,Tandem mass spectrometry ,Mass spectrometry ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Cystathionine ,Metabolomics ,Homoserine ,Homocysteine ,Lanthionine ,chemistry.chemical_classification ,010401 analytical chemistry ,Selected reaction monitoring ,equipment and supplies ,0104 chemical sciences ,Triple quadrupole mass spectrometer ,Amino acid ,030104 developmental biology ,chemistry ,Biochemistry ,Targeted analysis - Abstract
In the context of the vascular effects of hydrogen sulfide (H2S), it is known that this gaseous endogenous biological modulator of inflammation, oxidative stress, etc. is a potent vasodilator. Chronic renal failure, a common disease affecting the aging population, is characterized by low levels of H2S in plasma and tissues, which could mediate their typical hypertensive pattern, along with other abnormalities. Lanthionine and homolanthionine, natural non-proteinogenic amino acids, are formed as side products of H2S production. Also in consideration of the intrinsic difficulties in H2S measuring, these compounds have been proposed as reliable and stable markers of H2S synthesis. However, in the setting of chronic renal failure patients on hemodialysis, they represent typical retention products (without ruling out the possibility of an increased intestinal synthesis) and prospective novel uremic toxins. Here, a method utilizing liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring ion mode has been developed and evaluated for the determination of these key H2S metabolites in plasma, by using a triple quadrupole mass spectrometer.
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- 2019
45. Contributors
- Author
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Robert C. Albright, Richard Amerling, Paolo Angeli, Maria Lucia Angelotti, Massimo Antonelli, Riccardo Antoniotti, Nishkantha Arulkumaran, Pierre Asfar, Stephen R. Ash, Filippo Aucella, Francesco Aucella, Samuele Ave, Sean M. Bagshaw, Vasanthi Balaraman, Ian Baldwin, Joanne M. Bargman, Gina-Marie Barletta, Jeffrey F. Barletta, Shriganesh R. Barnela, Hülya Bayır, Monica Beaulieu, Antonio Bellasi, Rinaldo Bellomo, François Beloncle, Arjun Bhansali, Azra Bihorac, Frederic T. Billings, Horst-Walter Birk, Luis Ignacio Bonilla-Reséndiz, Josée Bouchard, Edmund Bourke, George Braitberg, Alessandra Brendolan, Alessandra Brocca, Patrick D. Brophy, Richard Bucala, Timothy E. Bunchman, Emmanuel A. Burdmann, Laurence W. Busse, Renato Antunes Caires, Pietro Caironi, Roberta Camilla, Israel Campos, Bernard Canaud, Vincenzo Cantaluppi, Maria P. Martinez, Giovambattista Capasso, Joseph A. Carcillo, Eleonora Carlesso, Francesco G. Casino, Giuseppe Castellano, Matteo Catania, Kelly A. Cawcutt, Jorge Cerda, Elliot Charen, Lakhmir S. Chawla, Stefano Chiaramonte, Horng-Ruey Chua, Bruno Cianciaruso, Paola Ciceri, Jacek Cieslak, William R. Clark, Rolando Claure-Del Granado, Anna Clementi, Ivan N. Co, Fernanda Oliveira Coelho, Ferruccio Conte, Howard E. Corey, Laura Cosmai, Elerson Carlos Costalonga, Andrea Costamagna, Maria Rosa Costanzo, Mario Cozzolino, Carl H. Cramer, Paolo Cravedi, Carlo Crepaldi, Jacques Creteur, R. John Crew, Verônica Torres da Costa e Silva, Andrew Davenport, Andrew R. Davies, Rohit D'Costa, Dawson F. Dean, Charlotte Debiais, Massimo de Cal, Paras Dedhia, Harm-Jan de Grooth, Roberto Dell'Aquila, Sergio Dellepiane, Richard Phillip Dellinger, Lucia Del Vecchio, Thomas A. Depner, Silvia De Rosa, Clifford S. Deutschman, Prasad Devarajan, A. Dewitte, Biagio R. Di Iorio, Luca Di Lullo, Lucia Di Micco, Matteo Di Nardo, Xiaoqiang Ding, Fiorella D'Ippoliti, Salvatore Di Somma, Kent Doi, David J. Dries, Wilfred Druml, Graeme Duke, Francois Durand, Michael T. Eadon, Devin Eckstein, Moritoki Egi, Somchai Eiam-Ong, Paul W.G. Elbers, Francesca Elli, Steve Elliott, David R. Emlet, Zoltan Endre, Roger G. Evans, Vito Fanelli, Fatemeh Fattahi, Christine Kinggaard Federspiel, Marcela A. Ferrada, Fiorenza Ferrari, Enrico Fiaccadori, Marco Fiorentino, Caleb Fisher, Michael F. Flessner, Marco Formica, Lui G. Forni, Claire Francoz, Craig French, Dana Y. Fuhrman, Giordano Fumagalli, Miriam Galbusera, Maurizio Gallieni, Hilary S. Gammill, Dayong Gao, Francesco Garzotto, Giuseppe Gatta, Kelly R. Genga, Simonetta Genovesi, Yuri S. Genyk, Christel Geradin, Loreto Gesualdo, Davide Giavarina, Anna Giuliani, Ilya G. Glezerman, Stuart L. Goldstein, Thomas A. Golper, Hernando Gómez, Antonio Granata, Giuseppe Grandaliano, Giacomo Grasselli, A.B. Johan Groeneveld, Philippe Guerci, Kyle J. Gunnerson, Nikolas Harbord, Lyndsay A. Harshman, Anthony J. Hennessy, Graham L. Hill, Charles Hobson, Bernd Hohenstein, Patrick M. Honoré, Edward Horwitz, Leila Hosseinian, Eric A.J. Hoste, Andrew A. House, H. David Humes, Faeq Husain-Syed, Can Ince, Todd S. Ing, Rita Jacobs, Dharmvir Jaswal, Arun Jeyabalan, Olivier Joannes-Boyau, Michael Joannidis, Emily Joyce, Sandra L. Kane-Gill, Lewis J. Kaplan, Kianoush Kashani, Nevin Katz, John A. Kellum, Ramesh Khanna, Nahmah Kim-Campbell, Joshua D. King, Christopher J. Kirwan, Joseph E. Kiss, David Klein, Peter Kotanko, Raymond T. Krediet, Martin K. Kuhlmann, Jan Willem Kuiper, Philippe Lachance, Norbert Lameire, Thomas Langer, Yugeesh R. Lankadeva, Louis-Philippe Laurin, Elena Lazzeri, Martine Leblanc, Joannie Lefebvre, Paolo Lentini, Hélène Leray-Moragués, Adeera Levin, Susie Q. Lew, Helen Liapis, Kathleen D. Liu, Sergio Livigni, Francesco Locatelli, Anna Lorenzin, Jian-Da Lu, Renhua Lu, Nicholas Lysak, Etienne Macedo, Niti Madan, François Madore, Linda L. Maerz, Matthew J. Maiden, Rakesh Malhotra, Marita Marengo, Filippo Mariano, Paul E. Marik, John J. Marini, Rossella Marino, Mark R. Marshall, Johan Mårtensson, Ryo Matsuura, Clive N. May, Patrizio Mazzone, Jerry McCauley, Peter A. McCullough, Blaithin A. McMahon, Ravindra L. Mehta, Caterina Mele, Madhav Menon, Mario Meola, Aicha Mérouani, Jean-Yves Meuwly, Paola Milla, Madhukar Misra, Paraish S. Misra, Barry A. Mizock, Jwalant R. Modi, Gilbert Moeckel, Bruce A. Molitoris, Santo Morabito, Roberto Pozzi Mucelli, Patrick T. Murray, Raghavan Murugan, Mitra K. Nadim, Devika Nair, Federico Nalesso, Mauro Neri, Trung C. Nguyen, Zhaohui Ni, Marina Noris, Tessa Novick, John C. O'Horo, Mark Douglas Okusa, Steven M. Opal, Helen Ingrid Opdam, Marlies Ostermann, Emerenziana Ottaviano, Heleen M. Oudemans-van Straaten, Christian Overgaard-Steensen, Massimo A. Padalino, Vincenzo Panichi, Priyanka Parameswaran, Samir S. Patel, Didier Payen, Federico Pea, W. Frank Peacock, Sandrica Young Peart, Sadudee Peerapornratana, Paolo Pelosi, Zhi-Yong Peng, Norberto Perico, Licia Peruzzi, Francesco Pesce, Antonio Pesenti, Ilaria Petrucci, Phuong-Chi Pham, Phuong-Thu Pham, Richard K.S. Phoon, Salvatore Piano, Michael R. Pinsky, Lise Piquilloud, Valentina Pistolesi, Lindsay D. Plank, Frans B. Plötz, Manuel Alfredo Podestá, Camillo Porta, Marco Pozzato, Michele Prencipe, John R. Prowle, Zudin A. Puthucheary, Lirong Qu, Jean-Sebastien Rachoin, Jai Radhakrishnan, V. Marco Ranieri, Ranistha Ratanarat, Giuseppe Remuzzi, Shelby Resnick, Oleksa G. Rewa, Zaccaria Ricci, Christophe Ridel, Kinan Rifai, Troels Ring, Lilia M. Rizo-Topete, Eric Roessler, Paola Romagnani, Stefano Romagnoli, Claudio Ronco, Federico Ronco, Mitchell H. Rosner, Emanuele Rossetti, James A. Russell, Georges Saab, Alice Sabatino, Sonali S. Saboo, Sara Samoni, Penny Lynn Sappington, Marco Sartori, Judy Savige, Francesco Paolo Schena, Antoine Guillaume Schneider, Pieter Schraverus, Wibke Schulte, Giuseppe Segoloni, Matthew W. Semler, Aashish Sharma, Andrew Shaw, Naitik Sheth, Ashutosh Shukla, Eric C. Siddall, Theodore M. Sievers, Edward D. Siew, Kai Singbartl, Mervyn Singer, Pooja Singh, Loren E. Smith, Sachin S. Soni, Mara Serrano Soto, Herbert D. Spapen, Nattachai Srisawat, Ajay Srivastava, Giovanni Stellin, Jordan M. Symons, Balazs Szamosfalvi, Kian Bun Tai, Unmesh V. Takalkar, Isaac Teitelbaum, Ciro Tetta, Charuhas V. Thakar, Marta Tonon, Francesco Trepiccione, Darrell Triulzi, Chopra Tushar, Shigehiko Uchino, Ali Valika, Wim Van Biesen, Wim Vandenberghe, Raymond Vanholder, Jill Vanmassenhove, Anton Verbine, Marco Vergano, Gianluca Villa, Pierre-Marc Villeneuve, Jean-Louis Vincent, Christophe Vinsonneau, Grazia Maria Virzì, Federico Visconti, Ravindran Visvanathan, Li Van Vong, Hans-Dieter Walmrath, Peter A. Ward, Matthew A. Weir, Xiaoyan Wen, Julia Wendon, James Frank Winchester, Adrian Wong, Elke L. Woodhouse, Jun Xue, Anju Yadav, Preethi Yerram, Lenar Yessayan, Jane Y. Yeun, Alex W. Yu, Marta Zaccaria, Miriam Zacchia, Teena P. Zachariah, Nereo Zamperetti, Fernando G. Zampieri, Pierluigi Zanco, Alberto Zanella, Luca Zanoli, Michael Zappitelli, Jose J. Zaragoza, Alexander Zarbock, Marta Zaroccolo, Han Zhang, and Andrea Zimmer
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- 2019
46. ERK1,2 signalling pathway along the nephron and its role in acid-base and electrolytes balance
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Yoko Suzumoto, Mariadelina Simeoni, Mariavittoria D'Acierno, Giovanna Capolongo, Giovambattista Capasso, Miriam Zacchia, Capolongo, G., Suzumoto, Y., D'Acierno, M., Simeoni, M., Capasso, G., and Zacchia, M.
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cell signaling ,medicine.medical_treatment ,030232 urology & nephrology ,Nephron ,Review ,lcsh:Chemistry ,Kidney Tubules, Proximal ,0302 clinical medicine ,Electrolyte ,Kidney Tubules, Distal ,lcsh:QH301-705.5 ,Spectroscopy ,Acid-Base Equilibrium ,Kidney ,Kinase ,Chemistry ,General Medicine ,Water-Electrolyte Balance ,Hedgehog signaling pathway ,Computer Science Applications ,Cell biology ,medicine.anatomical_structure ,Cytokine ,Disease Susceptibility ,Human ,MAP Kinase Signaling System ,Mesenchyme ,electrolytes ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Kidney Tubules, Collecting ,Molecular Biology ,Animal ,Organic Chemistry ,Nephrons ,MAPK ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Loop of Henle ,Acid-base ,ERK1,2 - Abstract
Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.
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- 2019
47. The role of the intestinal microbiota in uremic solute accumulation: a focus on sulfur compounds
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Evgeniya Anishchenko, Griet Glorieux, Carmela Vigorito, Alessandra F. Perna, Francesco Trepiccione, Giovanna Capolongo, Diego Ingrosso, Miriam Zacchia, Perna, A. F., Glorieux, G., Zacchia, M., Trepiccione, F., Capolongo, G., Vigorito, C., Anishchenko, E., and Ingrosso, D.
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Hydrogen sulfide ,030232 urology & nephrology ,chemistry.chemical_element ,030204 cardiovascular system & hematology ,Gut flora ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Folic Acid ,Chronic kidney disease ,Humans ,Medicine ,Sulfate ,Homocysteine ,Lanthionine ,Uremia ,Sulfane sulfur ,Sulfur Compound ,Sulfur Compounds ,biology ,business.industry ,Microbiota ,Dialysi ,medicine.disease ,biology.organism_classification ,Sulfur ,Gastrointestinal Microbiome ,Biochemistry ,chemistry ,Uremic toxin ,Nephrology ,Indoxyl Sulfate ,business ,Human - Abstract
The gut microbiota is considered to be a novel important factor to take into account in the pathogenesis of chronic kidney disease and uremia. Much attention has been paid to specific uremic retention solutes of microbial origin, such as indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide. However, other novel less well studied compounds, such as hydrogen sulfide and related sulfur metabolites (sulfane sulfur, lanthionine, etc.), should be included in a more comprehensive appraisal of this topic, in light of the potential therapeutic opportunities for the future.
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- 2019
48. The Physiology of the Loop of Henle
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Miriam Zacchia, Francesco Trepiccione, Giovambattista Capasso, Capasso, G., Trepiccione, F., Zacchia, M., Capasso, G., Trepiccione, F., and Zacchia, M.
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Sodium handling ,urogenital system ,Reabsorption ,Bicarbonate ,Sodium ,Acid-base homeostasi ,Furosemide ,chemistry.chemical_element ,Physiology ,Nephron ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Paracellular transport ,medicine ,Loop of Henle ,Potassium handling ,Thick ascending limb ,Homeostasis ,medicine.drug - Abstract
This chapter reports the morphology and function of the thick ascending limb (TAL) of the loop of Henle a crucial segment for many tasks of the nephron. Indeed, the TAL is a mainstay not only for the direct reabsorption of sodium, potassium, and divalent cations but also for its indirect role in the urine renal water reabsorption, overall acid-base homeostasis, and ammonia cycle. These functions are described in detail in this chapter, reporting in addition to the well-known mechanisms of action, innovative physiopathologic evidence. In an integrative way the mechanisms of sodium transport along the TAL are illustrated not only as functional to the paracellular uptake of cations but also as key element for the maintenance of the counter-current mechanism. TAL contributes to the acid-base homeostasis by reabsorbing bicarbonate. In addition to this classic view an innovative mechanism of acid secretion recently has been described in association with furosemide administration. Knowing the physiology of the TAL is fundamental for the clinicians who use loop diuretics. These are among the most commonly used drugs, but except the sodium loss, not all the physiologic consequences are known. This chapter attempts to fill this gap.
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- 2019
49. Zebrafish, a novel model system to study uremic toxins: The case for the sulfur amino acid lanthionine
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Miriam Zacchia, Salvatore D'Aniello, Evgeniya Anishchenko, Francesco Trepiccione, Carmela Vigorito, Diego Ingrosso, Alessandra F. Perna, Perna, A. F., Anishchenko, E., Vigorito, C., Zacchia, M., Trepiccione, F., D'Aniello, S., and Ingrosso, D.
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0301 basic medicine ,Organogenesi ,Organogenesis ,Transsulfuration ,lcsh:Chemistry ,chemistry.chemical_compound ,uremic toxin ,lanthionine ,uremia ,dialysis ,cardiovascular disease ,zebrafish ,glutathione ,Xenobiotic ,Zebrafish ,lcsh:QH301-705.5 ,Spectroscopy ,chemistry.chemical_classification ,Alanine ,biology ,Dialysi ,General Medicine ,Cardiovascular disease ,Glutathione ,3. Good health ,Computer Science Applications ,Amino acid ,Biochemistry ,Uremic toxin ,Lanthionine ,Sulfide ,Sulfides ,Catalysis ,Article ,Nitric oxide ,Xenobiotics ,Inorganic Chemistry ,03 medical and health sciences ,medicine ,Animals ,Physical and Theoretical Chemistry ,Molecular Biology ,Uremia ,Toxins, Biological ,Animal ,Organic Chemistry ,medicine.disease ,biology.organism_classification ,Disease Models, Animal ,030104 developmental biology ,Enzyme ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 - Abstract
The non-proteinogenic amino acid lanthionine is a byproduct of hydrogen sulfide biosynthesis: the third endogenous vasodilator gas, after nitric oxide and carbon monoxide. While hydrogen sulfide is decreased in uremic patients on hemodialysis, lanthionine is increased and has been proposed as a new uremic toxin, since it is able to impair hydrogen sulfide production in hepatoma cells. To characterize lanthionine as a uremic toxin, we explored its effects during the early development of the zebrafish (Danio rerio), a widely used model to study the organ and tissue alterations induced by xenobiotics. Lanthionine was employed at concentrations reproducing those previously detected in uremia. Light-induced visual motor response was also studied by means of the DanioVision system. Treatment of zebrafish embryos with lanthionine determined acute phenotypical alterations, on heart organogenesis (disproportion in cardiac chambers), increased heart beating, and arrhythmia. Lanthionine also induced locomotor alterations in zebrafish embryos. Some of these effects could be counteracted by glutathione. Lanthionine exerted acute effects on transsulfuration enzymes and the expression of genes involved in inflammation and metabolic regulation, and modified microRNA expression in a way comparable with some alterations detected in uremia. Lanthionine meets the criteria for classification as a uremic toxin. Zebrafish can be successfully used to explore uremic toxin effects.
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- 2018
50. Acid stimulation of the citrate transporter NaDC-1 requires Pyk2 and ERK1/2 signaling pathways
- Author
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Xuefei Tian, Robert J. Alpern, Miriam Zacchia, Enrica Zona, Patricia A. Preisig, Zacchia, Miriam, X2, Tian, E3, Zona, Rj2, Alpern, and Pa2., Preisig
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0301 basic medicine ,Kidney ,Cell signaling ,Brush border ,Chemistry ,030232 urology & nephrology ,Stimulation ,General Medicine ,Cell biology ,03 medical and health sciences ,Basic Research ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Nephrology ,In vivo ,medicine ,Phosphorylation ,Signal transduction ,Cotransporter - Abstract
Background Urine citrate is reabsorbed exclusively along the renal proximal tubule via the apical Na+-dicarboxylate cotransporter NaDC-1. We previously showed that an acid load in vivo and media acidification in vitro increase NaDC-1 activity through endothelin-1 (ET-1)/endothelin B (ETB) signaling. Here, we further examined the signaling pathway mediating acid-induced NaDC-1 activity.Methods We transiently transfected cultured opossum kidney cells, a model of the proximal tubule, with NaDC-1 and ETB and measured [14C]-citrate uptake after media acidification under various experimental conditions, including inactivation of Pyk2 and c-Src, which were previously shown to be activated by media acidification. Wild-type (Pyk2+/+) and Pyk2-null (Pyk2-/-) mice were exposed to NH4Cl loading and euthanized after various end points, at which time we harvested the kidneys for immunoblotting and brush border membrane NaDC-1 activity studies.Results Inhibition of Pyk2 or c-Src prevented acid stimulation but not ET-1 stimulation of NaDC-1 in vitro Consistent with these results, NH4Cl loading stimulated NaDC-1 activity in kidneys of wild-type but not Pyk2-/- mice. In cultured cells and in mice, ERK1/2 was rapidly phosphorylated by acid loading, even after Pyk2 knockdown, and it was required for acid but not ET-1/ETB stimulation of NaDC-1 in vitro Media acidification also induced the phosphorylation of Raf1 and p90RSK, components of the ERK1/2 pathway, and inhibition of these proteins blocked acid stimulation of NaDC-1 activity.Conclusions Acid stimulation of NaDC-1 activity involves Pyk2/c-Src and Raf1-ERK1/2-p90RSK signaling pathways, but these pathways are not downstream of ET-1/ETB in this process. Background Urine citrate is reabsorbed exclusively along the renal proximal tubule via the apical Na+-dicarboxylate cotransporter NaDC-1. We previously showed that an acid load in vivo and media acidification in vitro increase NaDC-1 activity through endothelin-1 (ET-1)/endothelin B (ETB) signaling. Here, we further examined the signaling pathway mediating acid-induced NaDC-1 activity. Methods We transiently transfected cultured opossum kidney cells, a model of the proximal tubule, with NaDC-1 and ETB and measured [14C]-citrate uptake after media acidification under various experimental conditions, including inactivation of Pyk2 and c-Src, which were previously shown to be activated by media acidification. Wild-type (Pyk2+/+) and Pyk2-null (Pyk22/2) mice were exposed to NH4Cl loading and euthanized after various end points, at which time we harvested the kidneys for immunoblotting and brush border membrane NaDC-1 activity studies. Results Inhibition of Pyk2 or c-Src prevented acid stimulation but not ET-1 stimulation of NaDC-1 in vitro. Consistent with these results, NH4Cl loading stimulated NaDC-1 activity in kidneys of wild-type but not Pyk22/2 mice. In cultured cells and in mice, ERK1/2 was rapidly phosphorylated by acid loading, even after Pyk2 knockdown, and it was required for acid but not ET-1/ETB stimulation of NaDC-1 in vitro. Media acidification also induced the phosphorylation of Raf1 and p90RSK, components of the ERK1/2 pathway, and inhibition of these proteins blocked acid stimulation of NaDC-1 activity. Conclusions Acid stimulation of NaDC-1 activity involves Pyk2/c-Src and Raf1-ERK1/2-p90RSK signaling pathways, but these pathways are not downstream of ET-1/ETB in this process.
- Published
- 2018
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