95 results on '"Mazzinghi B."'
Search Results
2. List of Contributors
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Agnoli, L., primary, Atkin, T., additional, Atwal, G., additional, Begalli, D., additional, Bouzdine-Chameeva, T., additional, Capitello, R., additional, Charters, S., additional, Cholette, S., additional, Cohen, J., additional, Corsi, A.M., additional, Cunha, N., additional, Curran, L., additional, Fang, Y., additional, Fountain, J., additional, Genand, M.-A., additional, Han, H., additional, Hanf, J.H., additional, Heine, K., additional, Liu, H., additional, Lockshin, L., additional, Loureiro, S.M.C., additional, Mazzinghi, B., additional, McCarthy, B., additional, Menival, D., additional, Seidemann, V., additional, Szolnoki, G., additional, Thorpe, M., additional, Winter, P., additional, Yang, H., additional, Yuan, J., additional, Zeng, L., additional, Zhang, W., additional, Zhang, X., additional, and Zhu, M., additional
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- 2017
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3. Therapeutic implications of novel mutations of the RFX6 gene associated with early-onset diabetes
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Artuso, R, Provenzano, A, Mazzinghi, B, Giunti, L, Palazzo, V, Andreucci, E, Blasetti, A, Chiuri, R M, Gianiorio, F E, Mandich, P, Monami, M, Mannucci, E, and Giglio, S
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- 2015
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4. Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells
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Antonelli, G, Angelotti, Ml, Allinovi, M, Guzzi, F, Sisti, A, Semeraro, R, Conte, C, Mazzinghi, B, Nardi, S, Melica, Me, De Chiara, L, Lazzeri, E, Lasagni, L, Lottini, T, Landini, S, Giglio, S, Mari, A, Di Maida, F, Antonelli, A, Porpiglia, F, Schiavina, R, Ficarra, V, Facchiano, D, Gacci, M, Serni, S, Carini, M, Netto, Gj, Roperto, Rm, Magi, A, Christiansen, Cf, Rotondi, M, Liapis, H, Anders, Hj, Minervini, A, Raspollini, Mr, and Romagnani, P.
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Acute kidney injury, renal cell carcinoma, renal progenitors - Published
- 2020
5. Chapter 15 - Practice Viewpoint: The Chinese Way
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Mazzinghi, B.
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- 2017
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6. TTRV30M oligomeric aggregates inhibit proliferation of renal progenitor cells but maintain their capacity to differentiate into podocytes in vitro
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Moreira, L., Ballerini, L., Peired, A., Sagrinati, C., Parente, E., Angelotti, M.L., Ronconi, E., Lazzeri, E., Mazzinghi, B., Lacerda, P., Beirão, I., Lasagni, L., Costa, P.P., and Romagnani, P.
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Familial Amyloidotic Polyneuropathy ,Renal Progenitor Cells ,sense organs ,Renal Disease ,Transthyretin ,Doenças Genéticas - Abstract
Publicado em: The Proceedings of the XIIIth International Symposium on Amyloidosis, May 6-10, 2012, Groningen, The Netherlands In Familial Amyloidotic Polyneuropathy, the amyloid deposition of mutant transthyretin TTR V30M can lead to renal complications. An unexplored mechanism is the toxicity of oligomeric TTR aggregates. A subset of renal progenitor cells (RPC) in the adult human kidney can induce regeneration of podocytes and tubular structures of the nephron, which can be critical for preventing irreversible renal failure. We assessed whether RPC are vulnerable, in vitro, to TTRV30M oligomers. RPC proliferation was reduced by 16.3±9.7% and 32.6±6.3% after 48 and 72 hours, respectively, in the presence of the oligomers. However, oligomers did not induce apoptosis or alterations in cell cycle to any significant extent, and did not influence RPC differentiation into podocytes. From this first attempt, we can say that TTRV30M oligomers inhibit RPC proliferation but do not influence their capacity to differentiate into mature podocytes, and thus should not compromise tissue regeneration. FCT
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- 2012
7. Regeneration and the kidney
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Lazzeri E, Mazzinghi B, and Romagnani P.
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- 2010
8. Resistin as an Intrahepatic Cytokine : Overexpression during Chronic Injury and Induction of Proinflammatory Actions in Hepatic Stellate Cells
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Bertolani, C, SANCHO BRU, P, Failli, P, Bataller, R, Aleffi, S, Defranco, R, Mazzinghi, B, Romagnani, P, Milani, S, Gins, P, Colmenero, J, Parola, Maurizio, Gelmini, S, Tarquini, R, Laffi, G, Pinzani, M, and Marra, F.
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Inflammation ,endocrine system diseases ,Hepatitis, Alcoholic ,Liver Diseases ,NF-kappa B ,nutritional and metabolic diseases ,respiratory system ,Up-Regulation ,Liver ,Case-Control Studies ,Acute Disease ,Humans ,Calcium ,Resistin ,Chemokines ,hormones, hormone substitutes, and hormone antagonists ,Cells, Cultured ,Regular Articles ,Signal Transduction - Abstract
Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-kappaB. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-kappaB activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca2+/NF-kappaB-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis.
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- 2006
9. Calcium-dependent activation of NF-κB by the adipokine resistin in human hepatic stellate cells
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Bertolani, C., Petrai, I., Aleffi, S., Failli, P., Mazzinghi, B., Romagnani, P., Orlando, C., Gelmini, S., Defranco, R., Pinzani, M., Parola, Maurizio, and Marra, F. .
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- 2005
10. Calcium – dependent activation of NF-kB by the adipokine resistin in hepatic stellate cells
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Bertolani, C., Petrai, I., Aleffi, S., Failli, P., Mazzinghi, B., Romagnani, P., Orlando, C., Gelmini, S., Defranco, R., Pinzani, M., Parola, Maurizio, and Marra, F.
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- 2005
11. Calcium-dependent activation of NF-kappa B by the adipokine resistin in hepatic stellate cells
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Bertolani, C., Petrai, I., Aleffi, S., Failli, P., Mazzinghi, B., Romagnani, P., Orlando, C., Gelmini, S., Defranco, R., Pinzani, M., Parola, M., and Marra, F.
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virus diseases ,digestive system diseases - Published
- 2005
12. Therapeutic implications of novel mutations of the RFX6 gene associated with early-onset diabetes
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Artuso, R, primary, Provenzano, A, additional, Mazzinghi, B, additional, Giunti, L, additional, Palazzo, V, additional, Andreucci, E, additional, Blasetti, A, additional, Chiuri, R M, additional, Gianiorio, F E, additional, Mandich, P, additional, Monami, M, additional, Mannucci, E, additional, and Giglio, S, additional
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- 2014
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13. Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes
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Crescioli, C, primary, Cosmi, L, additional, Borgogni, E, additional, Santarlasci, V, additional, Gelmini, S, additional, Sottili, M, additional, Sarchielli, E, additional, Mazzinghi, B, additional, Francalanci, M, additional, Pezzatini, A, additional, Perigli, G, additional, Vannelli, G B, additional, Annunziato, F, additional, and Serio, M, additional
- Published
- 2007
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14. Pharmacological Modulation of Stem Cell Function
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Romagnani, P., primary, Lasagni, L., additional, Mazzinghi, B., additional, Lazzeri, E., additional, and Romagnani, S., additional
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- 2007
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15. CXCR3-mediated opposite effects of CXCL10 and CXCL4 on T1 or T2 cytokine production
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ROMAGNANI, P, primary, MAGGI, L, additional, MAZZINGHI, B, additional, COSMI, L, additional, LASAGNI, L, additional, LIOTTA, F, additional, LAZZERI, E, additional, ANGELI, R, additional, ROTONDI, M, additional, and FILI, L, additional
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- 2005
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16. 324 Differential expression of two isoforms of the chemokine receptor CXCR3 determines the ultimate effect of IP-10 on survival of human hepatic stellate cells (HSC)
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Petrai, I., primary, Bonacchi, A., additional, Romagnani, P., additional, Parola, M., additional, Mazzinghi, B., additional, Rotondi, M., additional, Failli, P., additional, Aleffi, S., additional, Bertolani, C., additional, Novo, E., additional, Zamara, E., additional, Pinzani, M., additional, Laffi, G., additional, Gentilini, P., additional, and Marra, F., additional
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- 2004
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17. Some protein tyrosine phosphatases target in part to lipid rafts and interact with caveolin-1
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Caselli, A, primary, Mazzinghi, B, additional, Camici, G, additional, Manao, G, additional, and Ramponi, G, additional
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- 2002
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18. RUOLO DEL DANNO PODOCITARIO NELLA PATOGENESI DELLA GLOMERULOSCLEROSI E POSSIBILI MECCANISMI DI RIPARAZIONE.
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Ronconi, E., Mazzinghi, B., Sagrinati, C., Angelotti, M. L., Ballerini, L., Parente, E., Romagnani, P., Lazzeri, E., and Lasagni, L.
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- 2009
19. RUOLO DEI PROGENITORI ENDOTELIALI NELLE MALATTIE RENALI.
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Lazzeri, E., Angelotti, M. L., Ballerini, L., Becherucci, F., Mazzinghi, B., Parente, E., Ronconi, E., Sagrinati, C., Romagnani, P., and Lasagni, L.
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- 2008
20. [Tubular progenitor cells: new protagonists of tubular regeneration].,Cellule progenitrici tubulari: nuovi protagonisti per la rigenerazione tubulare renale
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Angelotti, M. L., Ronconi, E., Peired, A., Mazzinghi, B., Elena LAZZERI, Lasagni, L., and Romagnani, P.
21. Chemokines: possible therapeutic targets and useful clinical parameters in renal transplantation,Le chemochine nel trapianto renale: possibili bersagli terapeutici e nuovi parametri clinici
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Mazzinghi, B., Netti, G. S., Lazzeri, E., and Paola Romagnani
22. The role of podocyte damage in the pathogenesis of glomerulosclerosis and possible repair mechanisms,Ruolo del danno podocitario nella patogenesi della glomerulosclerosi e possibili meccanismi di riparazione
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Ronconi, E., Mazzinghi, B., Sagrinati, C., Angelotti, M. L., Ballerini, L., Parente, E., Romagnani, P., Elena LAZZERI, and Lasagni, L.
23. [Tubular progenitor cells: new protagonists of tubular regeneration]. | Cellule progenitrici tubulari: nuovi protagonisti per la rigenerazione tubulare renale
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Angelotti, M. L., Ronconi, E., Anna Peired, Mazzinghi, B., Lazzeri, E., Lasagni, L., and Romagnani, P.
24. The role of endothelial progenitor cells in renal disease | Ruolo dei progenitori endoteliali nelle malattie renali
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Lazzeri, E., Angelotti, M. L., Ballerini, L., Becherucci, F., Mazzinghi, B., Parente, E., Ronconi, E., Sagrinati, C., Paola Romagnani, and Lasagni, L.
25. Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells
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Hans-Joachim Anders, Alessandro Antonelli, Tiziano Lottini, Andrea Minervini, Marco Carini, Francesco Guzzi, Paola Romagnani, Mauro Gacci, Alessandro Sisti, Carolina Conte, Fabrizio Di Maida, Mario Rotondi, Samuela Landini, Marco Allinovi, Maria Elena Melica, Rosa Maria Roperto, Francesco Porpiglia, Vincenzo Ficarra, Benedetta Mazzinghi, Sergio Serni, Sabrina Giglio, George J. Netto, Maria Rosaria Raspollini, Maria Lucia Angelotti, Letizia De Chiara, Sara Nardi, Giulia Antonelli, Davide Facchiano, Alberto Magi, Riccardo Schiavina, Elena Lazzeri, Helen Liapis, Andrea Mari, Roberto Semeraro, Christian Fynbo Christiansen, Laura Lasagni, Anna Julie Peired, Peired A.J., Antonelli G., Angelotti M.L., Allinovi M., Guzzi F., Sisti A., Semeraro R., Conte C., Mazzinghi B., Nardi S., Melica M.E., De Chiara L., Lazzeri E., Lasagni L., Lottini T., Landini S., Giglio S., Mari A., Di Maida F., Antonelli A., Porpiglia F., Schiavina R., Ficarra V., Facchiano D., Gacci M., Serni S., Carini M., Netto G.J., Roperto R.M., Magi A., Christiansen C.F., Rotondi M., Liapis H., Anders H.-J., Minervini A., Raspollini M.R., and Romagnani P.
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Adenoma ,0301 basic medicine ,papillary renal cell carcinoma ,medicine.disease_cause ,urologic and male genital diseases ,DISEASE ,PATHWAY ,PROTECTS ,Mice ,03 medical and health sciences ,0302 clinical medicine ,AKI ,NOTCH1 ,REGENERATION ,Renal cell carcinoma ,Biomarkers, Tumor ,ABLATION ,medicine ,Carcinoma ,Animals ,Progenitor cell ,RECURRENCE ,Carcinoma, Renal Cell ,RECEPTOR ,Papillary renal cell carcinomas ,business.industry ,Stem Cells ,Papillary Adenoma ,Acute kidney injury ,renal carcinoma ,General Medicine ,Acute Kidney Injury ,medicine.disease ,TUMORS ,Kidney Neoplasms ,3. Good health ,NOTCH ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,GROWTH ,Neoplasm Recurrence, Local ,Stem cell ,Carcinogenesis ,business - Abstract
Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.
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26. Renal Progenitors Derived from Urine for Personalized Diagnosis of Kidney Diseases.
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Mazzinghi B, Melica ME, Lasagni L, Romagnani P, and Lazzeri E
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- Humans, Kidney Diseases diagnosis, Kidney Diseases urine, Kidney pathology, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic urine, Urine cytology, Precision Medicine, Stem Cells
- Abstract
Background: Chronic kidney disease affects 10% of the world population, and it is associated with progression to end-stage kidney disease and increased morbidity and mortality. The advent of multi-omics technologies has expanded our knowledge on the complexity of kidney diseases, revealing their frequent genetic etiology, particularly in children and young subjects. Genetic heterogeneity and drug screening require patient-derived disease models to establish a correct diagnosis and evaluate new potential treatments and outcomes., Summary: Patient-derived renal progenitors can be isolated from urine to set up proper disease modeling. This strategy allows to make diagnosis of genetic kidney disease in patients carrying unknown significance variants or uncover variants missed from peripheral blood analysis. Furthermore, urinary-derived tubuloids obtained from renal progenitors of patients appear to be potentially valuable for modeling kidney diseases to test ex vivo treatment efficacy or to develop new therapeutic approaches. Finally, renal progenitors derived from urine can provide insights into acute kidney injury and predict kidney function recovery and outcome., Key Messages: Renal progenitors derived from urine are a promising new noninvasive and easy-to-handle tool, which improves the rate of diagnosis and the therapeutic choice, paving the way toward a personalized healthcare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)
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- 2024
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27. Polyploid tubular cells initiate a TGF-β1 controlled loop that sustains polyploidization and fibrosis after acute kidney injury.
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De Chiara L, Semeraro R, Mazzinghi B, Landini S, Molli A, Antonelli G, Angelotti ML, Melica ME, Maggi L, Conte C, Peired AJ, Cirillo L, Raglianti V, Magi A, Annunziato F, Romagnani P, and Lazzeri E
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- Animals, Mice, Epithelial Cells, Polyploidy, Fibrosis, Transforming Growth Factor beta1 genetics, Acute Kidney Injury genetics
- Abstract
Polyploidization of tubular cells (TC) is triggered by acute kidney injury (AKI) to allow survival in the early phase after AKI, but in the long run promotes fibrosis and AKI-chronic kidney disease (CKD) transition. The molecular mechanism governing the link between polyploid TC and kidney fibrosis remains to be clarified. In this study, we demonstrate that immediately after AKI, expression of cell cycle markers mostly identifies a population of DNA-damaged polyploid TC. Using transgenic mouse models and single-cell RNA sequencing we show that, unlike diploid TC, polyploid TC accumulate DNA damage and survive, eventually resting in the G1 phase of the cell cycle. In vivo and in vitro single-cell RNA sequencing along with sorting of polyploid TC shows that these cells acquire a profibrotic phenotype culminating in transforming growth factor (TGF)-β1 expression and that TGF-β1 directly promotes polyploidization. This demonstrates that TC polyploidization is a self-sustained mechanism. Interactome analysis by single-cell RNA sequencing revealed that TGF-β1 signaling fosters a reciprocal activation loop among polyploid TC, macrophages, and fibroblasts to sustain kidney fibrosis and promote CKD progression. Collectively, this study contributes to the ongoing revision of the paradigm of kidney tubule response to AKI, supporting the existence of a tubulointerstitial cross talk mediated by TGF-β1 signaling produced by polyploid TC following DNA damage. NEW & NOTEWORTHY Polyploidization in tubular epithelial cells has been neglected until recently. Here, we showed that polyploidization is a self-sustained mechanism that plays an important role during chronic kidney disease development, proving the existence of a cross talk between infiltrating cells and polyploid tubular cells. This study contributes to the ongoing revision of kidney adaptation to injury, posing polyploid tubular cells at the center of the process.
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- 2023
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28. Preparation of Human Kidney Progenitor Cultures and Their Differentiation into Podocytes.
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Melica ME, Angelotti ML, Antonelli G, Peired AJ, Conte C, De Chiara L, Mazzinghi B, Lazzeri E, Lasagni L, and Romagnani P
- Abstract
Kidney diseases are a global health concern. Modeling of kidney disease for translational research is often challenging because of species specificities or the postmitotic status of kidney epithelial cells that make primary cultures, for example podocytes. Here, we report a protocol for preparing primary cultures of podocytes based on the isolation and in vitro propagation of immature kidney progenitor cells subsequently differentiated into mature podocytes. This protocol can be useful for studying physiology and pathophysiology of human kidney progenitors and to obtain differentiated podocytes for modeling podocytopathies and other kidney disorders involving podocytes., Competing Interests: Competing interestsThe authors have no competing financial interests., (©Copyright : © 2023 The Authors; This is an open access article under the CC BY license.)
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- 2023
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29. A Clinical Workflow for Cost-Saving High-Rate Diagnosis of Genetic Kidney Diseases.
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Becherucci F, Landini S, Palazzo V, Cirillo L, Raglianti V, Lugli G, Tiberi L, Dirupo E, Bellelli S, Mazzierli T, Lomi J, Ravaglia F, Sansavini G, Allinovi M, Giannese D, Somma C, Spatoliatore G, Vergani D, Artuso R, Rosati A, Cirami C, Dattolo PC, Campolo G, De Chiara L, Papi L, Vaglio A, Lazzeri E, Anders HJ, Mazzinghi B, and Romagnani P
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- Adult, Infant, Newborn, Humans, Child, Workflow, Kidney, Genetic Testing, Urinary Tract, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic genetics
- Abstract
Significance Statement: To optimize the diagnosis of genetic kidney disorders in a cost-effective manner, we developed a workflow based on referral criteria for in-person evaluation at a tertiary center, whole-exome sequencing, reverse phenotyping, and multidisciplinary board analysis. This workflow reached a diagnostic rate of 67%, with 48% confirming and 19% modifying the suspected clinical diagnosis. We obtained a genetic diagnosis in 64% of children and 70% of adults. A modeled cost analysis demonstrated that early genetic testing saves 20% of costs per patient. Real cost analysis on a representative sample of 66 patients demonstrated an actual cost reduction of 41%. This workflow demonstrates feasibility, performance, and economic effect for the diagnosis of genetic kidney diseases in a real-world setting., Background: Whole-exome sequencing (WES) increases the diagnostic rate of genetic kidney disorders, but accessibility, interpretation of results, and costs limit use in daily practice., Methods: Univariable analysis of a historical cohort of 392 patients who underwent WES for kidney diseases showed that resistance to treatments, familial history of kidney disease, extrarenal involvement, congenital abnormalities of the kidney and urinary tract and CKD stage ≥G2, two or more cysts per kidney on ultrasound, persistent hyperechoic kidneys or nephrocalcinosis on ultrasound, and persistent metabolic abnormalities were most predictive for genetic diagnosis. We prospectively applied these criteria to select patients in a network of nephrology centers, followed by centralized genetic diagnosis by WES, reverse phenotyping, and multidisciplinary board discussion., Results: We applied this multistep workflow to 476 patients with eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorders), obtaining genetic diagnosis for 319 of 476 patients (67.0%) (95% in 21 patients with disease onset during the fetal period or at birth, 64% in 298 pediatric patients, and 70% in 156 adult patients). The suspected clinical diagnosis was confirmed in 48% of the 476 patients and modified in 19%. A modeled cost analysis showed that application of this workflow saved 20% of costs per patient when performed at the beginning of the diagnostic process. Real cost analysis of 66 patients randomly selected from all categories showed actual cost reduction of 41%., Conclusions: A diagnostic workflow for genetic kidney diseases that includes WES is cost-saving, especially if implemented early, and is feasible in a real-world setting., (Copyright © 2023 by the American Society of Nephrology.)
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- 2023
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30. Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease.
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De Chiara L, Conte C, Semeraro R, Diaz-Bulnes P, Angelotti ML, Mazzinghi B, Molli A, Antonelli G, Landini S, Melica ME, Peired AJ, Maggi L, Donati M, La Regina G, Allinovi M, Ravaglia F, Guasti D, Bani D, Cirillo L, Becherucci F, Guzzi F, Magi A, Annunziato F, Lasagni L, Anders HJ, Lazzeri E, and Romagnani P
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- DNA metabolism, Disease Progression, Humans, Kidney metabolism, Polyploidy, RNA metabolism, Senotherapeutics, Acute Kidney Injury metabolism, Renal Insufficiency, Chronic genetics, Renal Insufficiency, Chronic metabolism
- Abstract
Acute kidney injury (AKI) is frequent, often fatal and, for lack of specific therapies, can leave survivors with chronic kidney disease (CKD). We characterize the distribution of tubular cells (TC) undergoing polyploidy along AKI by DNA content analysis and single cell RNA-sequencing. Furthermore, we study the functional roles of polyploidization using transgenic models and drug interventions. We identify YAP1-driven TC polyploidization outside the site of injury as a rapid way to sustain residual kidney function early during AKI. This survival mechanism comes at the cost of senescence of polyploid TC promoting interstitial fibrosis and CKD in AKI survivors. However, targeting TC polyploidization after the early AKI phase can prevent AKI-CKD transition without influencing AKI lethality. Senolytic treatment prevents CKD by blocking repeated TC polyploidization cycles. These results revise the current pathophysiological concept of how the kidney responds to acute injury and identify a novel druggable target to improve prognosis in AKI survivors., (© 2022. The Author(s).)
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- 2022
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31. Differentiation of crescent-forming kidney progenitor cells into podocytes attenuates severe glomerulonephritis in mice.
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Melica ME, Antonelli G, Semeraro R, Angelotti ML, Lugli G, Landini S, Ravaglia F, Regina G, Conte C, De Chiara L, Peired AJ, Mazzinghi B, Donati M, Molli A, Steiger S, Magi A, Bartalucci N, Raglianti V, Guzzi F, Maggi L, Annunziato F, Burger A, Lazzeri E, Anders HJ, Lasagni L, and Romagnani P
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- Animals, Disease Models, Animal, Humans, Kidney metabolism, Mice, Panobinostat therapeutic use, Stem Cells metabolism, Glomerulonephritis drug therapy, Podocytes metabolism
- Abstract
Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the formation of crescents. Little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in two Pax2Cre reporter mouse models revealed that crescents derive from clonal expansion of single immature parietal epithelial cells. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used to treat hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis with recovery of kidney function in the two mouse models. Three-dimensional confocal microscopy and stimulated emission depletion superresolution imaging of mouse glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat induced differentiation of an immature hyperplastic parietal epithelial cell subset into podocytes, thereby restoring the glomerular filtration barrier. Single-cell RNA sequencing of human renal progenitor cells in vitro identified an immature stratifin-positive cell subset and revealed that expansion of this stratifin-expressing progenitor cell subset was associated with a poor outcome in human crescentic glomerulonephritis. Treatment of human parietal epithelial cells in vitro with panobinostat attenuated stratifin expression in renal progenitor cells, reduced their proliferation, and promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of renal progenitor cells can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis in mice.
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- 2022
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32. Clinical and Genetic Characterization of Patients with Bartter and Gitelman Syndrome.
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Palazzo V, Raglianti V, Landini S, Cirillo L, Errichiello C, Buti E, Artuso R, Tiberi L, Vergani D, Dirupo E, Romagnani P, Mazzinghi B, and Becherucci F
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- DNA Copy Number Variations, Female, Humans, Infant, Newborn, Bartter Syndrome diagnosis, Bartter Syndrome genetics, Gitelman Syndrome diagnosis, Gitelman Syndrome genetics, Premature Birth, Renal Insufficiency, Chronic
- Abstract
Bartter (BS) and Gitelman (GS) syndrome are autosomal recessive inherited tubulopathies, whose clinical diagnosis can be challenging, due to rarity and phenotypic overlap. Genotype-phenotype correlations have important implications in defining kidney and global outcomes. The aim of our study was to assess the diagnostic rate of whole-exome sequencing (WES) coupled with a bioinformatic analysis of copy number variations in a population of 63 patients with BS and GS from a single institution, and to explore genotype-phenotype correlations. We obtained a diagnostic yield of 86% (54/63 patients), allowing disease reclassification in about 14% of patients. Although some clinical and laboratory features were more commonly reported in patients with BS or GS, a significant overlap does exist, and age at onset, preterm birth, gestational age and nephro-calcinosis are frequently misleading. Finally, chronic kidney disease (CKD) occurs in about 30% of patients with BS or GS, suggesting that the long-term prognosis can be unfavorable. In our cohort the features associated with CKD were lower gestational age at birth and a molecular diagnosis of BS, especially BS type 1. The results of our study demonstrate that WES is useful in dealing with the phenotypic heterogeneity of these disorders, improving differential diagnosis and genotype-phenotype correlation.
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- 2022
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33. Erratum to: MO065 tubular epithelial cell polyploidization is required to survive AKI but promotes CKD development.
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De Chiara L, Lazzeri E, Angelotti ML, Conte C, Peired AJ, Antonelli G, Melica ME, Mazzinghi B, Lasagni L, and Romagnani P
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- 2022
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34. Look Alike, Sound Alike: Phenocopies in Steroid-Resistant Nephrotic Syndrome.
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Becherucci F, Landini S, Cirillo L, Mazzinghi B, and Romagnani P
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- Drug Resistance, Genetic Testing standards, Humans, Mutation, Steroids therapeutic use, Nephrotic Syndrome drug therapy, Nephrotic Syndrome genetics, Phenotype
- Abstract
Steroid-resistant nephrotic syndrome (SRNS) is a clinical picture defined by the lack of response to standard steroid treatment, frequently progressing toward end-stage kidney disease. The genetic basis of SRNS has been thoroughly explored since the end of the 1990s and especially with the advent of next-generation sequencing. Genetic forms represent about 30% of cases of SRNS. However, recent evidence supports the hypothesis that "phenocopies" could account for a non-negligible fraction of SRNS patients who are currently classified as non-genetic, paving the way for a more comprehensive understanding of the genetic background of the disease. The identification of phenocopies is mandatory in order to provide patients with appropriate clinical management and to inform therapy. Extended genetic testing including phenocopy genes, coupled with reverse phenotyping, is recommended for all young patients with SRNS to avoid unnecessary and potentially harmful diagnostic procedures and treatment, and for the reclassification of the disease. The aim of this work is to review the main steps of the evolution of genetic testing in SRNS, demonstrating how a paradigm shifting from "forward" to "reverse" genetics could significantly improve the identification of the molecular mechanisms of the disease, as well as the overall clinical management of affected patients.
- Published
- 2020
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35. Bioengineering strategies for nephrologists: kidney was not built in a day.
- Author
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Peired AJ, Mazzinghi B, De Chiara L, Guzzi F, Lasagni L, Romagnani P, and Lazzeri E
- Subjects
- Animals, Artificial Organs, Humans, Kidney Failure, Chronic therapy, Kidney Transplantation, Printing, Three-Dimensional, Tissue Scaffolds, Transplantation, Heterologous, Bioengineering, Kidney physiology
- Abstract
Introduction : The number of patients with end-stage kidney disease is increasing worldwide, creating an unprecedented organ shortage. The kidney is a highly complex structure performing many crucial functions. Dialysis replaces filtration but not all other kidney functions and transplant is limited by kidney availability. Numerous innovative ways are being explored to obtain new kidneys for disease modeling and potentially replace lost kidney functions. Areas covered : In this review, we will go through the different approaches that have been developed over the years to build kidneys. We will first present the current advances in xenotransplantation and generation of interspecies chimeras. Next, we will examine the attempts to create bioengineered kidneys with hemodialysis-derived implantable devices and decellularized organs. Finally, we will examine how organoids and microfluidic devices could answer important pathophysiological questions and model the path toward creating in vitro functional organs, for example through 3D bioprinting. Expert opinion : While all the aforementioned approaches to create new kidneys are promising, their translation into clinical practice seems a long way off, except xenotransplantation. Nonetheless, these novel technologies already consent disease modeling and drug testing at 3D level. We will review the stages of progress toward patient therapy and advantages/drawbacks of the various strategies.
- Published
- 2020
- Full Text
- View/download PDF
36. Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.
- Author
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Peired AJ, Antonelli G, Angelotti ML, Allinovi M, Guzzi F, Sisti A, Semeraro R, Conte C, Mazzinghi B, Nardi S, Melica ME, De Chiara L, Lazzeri E, Lasagni L, Lottini T, Landini S, Giglio S, Mari A, Di Maida F, Antonelli A, Porpiglia F, Schiavina R, Ficarra V, Facchiano D, Gacci M, Serni S, Carini M, Netto GJ, Roperto RM, Magi A, Christiansen CF, Rotondi M, Liapis H, Anders HJ, Minervini A, Raspollini MR, and Romagnani P
- Subjects
- Animals, Biomarkers, Tumor, Mice, Neoplasm Recurrence, Local, Stem Cells, Acute Kidney Injury, Adenoma genetics, Carcinoma, Renal Cell genetics, Kidney Neoplasms genetics
- Abstract
Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
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37. Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome.
- Author
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Landini S, Mazzinghi B, Becherucci F, Allinovi M, Provenzano A, Palazzo V, Ravaglia F, Artuso R, Bosi E, Stagi S, Sansavini G, Guzzi F, Cirillo L, Vaglio A, Murer L, Peruzzi L, Pasini A, Materassi M, Roperto RM, Anders HJ, Rotondi M, Giglio SR, and Romagnani P
- Subjects
- Biopsy, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Kidney Function Tests, Kidney Transplantation, Male, Nephrotic Syndrome diagnosis, Nephrotic Syndrome genetics, Nephrotic Syndrome surgery, Phenotype, Predictive Value of Tests, Prognosis, Reproducibility of Results, Retrospective Studies, Workflow, Genetic Variation, Nephrotic Syndrome congenital, Exome Sequencing
- Abstract
Background and Objectives: Nephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients., Design, Setting, Participants, & Measurements: All patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and in silico filtering of 298 genes related to CKD were combined with subsequent reverse phenotyping in patients and families. Pathogenic variants were defined according to current guidelines of the American College of Medical Genetics., Results: A total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies., Conclusions: Reverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome., (Copyright © 2020 by the American Society of Nephrology.)
- Published
- 2020
- Full Text
- View/download PDF
38. A microRNA profile of pediatric glioblastoma: The role of NUCKS1 upregulation.
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Giunti L, Da Ros M, De Gregorio V, Magi A, Landini S, Mazzinghi B, Buccoliero AM, Genitori L, Giglio S, and Sardi I
- Abstract
MicroRNAs (miRNAs/miRs) are a novel class of gene regulators that may be involved in tumor chemoresistance. Recently, specific miRNA expression profiles have been identified in adult glioblastoma (aGBM), but there are only limited data available on the role of miRNAs in pediatric GBM (pGBM). In the present study, the expression profile of miRNAs was examined in seven pGBMs and three human GBM cell lines (U87MG, A172 and T98G), compared with a non-tumoral pool of pediatric cerebral cortex samples by microarray analysis. A set of differentially expressed miRNAs was identified, including miR-490, miR-876-3p, miR-876-5p, miR-448 and miR-137 (downregulated), as well as miR-501-3p (upregulated). Through bioinformatics analysis, a series of target genes was predicted. In addition, similar gene expression patterns in pGBMs and cell lines was confirmed. Of note, drug resistant T98G cells had upregulated nuclear casein kinase and cyclin-dependent kinase substrate 1 ( NUCKS1 ) expression, a protein overexpressed in many tumors that serves an important role in cell proliferation and progression. On the basis of the present preliminary report, it could be intriguing to further investigate the relationship between each of the identified differentially expressed miRNAs and NUCKS1, in order to clarify their involvement in the multi-drug resistance mechanism of pGBMs.
- Published
- 2019
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39. Regenerating the kidney using human pluripotent stem cells and renal progenitors.
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Becherucci F, Mazzinghi B, Allinovi M, Angelotti ML, and Romagnani P
- Subjects
- Animals, Cell Differentiation, Embryonic Stem Cells, Humans, Induced Pluripotent Stem Cells physiology, Induced Pluripotent Stem Cells transplantation, Pluripotent Stem Cells physiology, Stem Cell Transplantation methods, Kidney physiology, Pluripotent Stem Cells transplantation, Regeneration physiology, Renal Insufficiency, Chronic therapy, Stem Cells physiology
- Abstract
Introduction: Chronic kidney disease is a major health-care problem worldwide and its cost is becoming no longer affordable. Indeed, restoring damaged renal structures or building a new kidney represents an ambitious and ideal alternative to renal replacement therapy. Streams of research have explored the possible application of pluripotent stem cells (SCs) (embryonic SCs and induced pluripotent SCs) in different strategies aimed at regenerate functioning nephrons and at understanding the mechanisms of kidney regeneration., Areas Covered: In this review, we will focus on the main potential applications of human pluripotent SCs to kidney regeneration, including those leading to rebuilding new kidneys or part of them (organoids, scaffolds, biological microdevices) as well as those aimed at understanding the pathophysiological mechanisms of renal disease and regenerative processes (modeling of kidney disease, genome editing). Moreover, we will discuss the role of endogenous renal progenitors cells in order to understand and promote kidney regeneration, as an attractive alternative to pluripotent SCs., Expert Opinion: Opportunities and pitfalls of all these strategies will be underlined, finally leading to the conclusion that a deeper knowledge of the biology of pluripotent SCs is mandatory, in order to allow us to hypothesize their clinical application.
- Published
- 2018
- Full Text
- View/download PDF
40. Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury.
- Author
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Lazzeri E, Angelotti ML, Peired A, Conte C, Marschner JA, Maggi L, Mazzinghi B, Lombardi D, Melica ME, Nardi S, Ronconi E, Sisti A, Antonelli G, Becherucci F, De Chiara L, Guevara RR, Burger A, Schaefer B, Annunziato F, Anders HJ, Lasagni L, and Romagnani P
- Subjects
- Acute Kidney Injury genetics, Adult Stem Cells pathology, Animals, Cell Cycle, Cell Dedifferentiation, Cell Enlargement, Cell Lineage, Epithelial Cells drug effects, Epithelial Cells pathology, Female, Histone Deacetylase Inhibitors pharmacology, Humans, Kidney Tubules drug effects, Kidney Tubules pathology, Kidney Tubules physiopathology, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, PAX2 Transcription Factor metabolism, PAX8 Transcription Factor metabolism, Ploidies, Regeneration drug effects, Single-Cell Analysis, Acute Kidney Injury pathology, Acute Kidney Injury physiopathology
- Abstract
Acute kidney injury (AKI) is considered largely reversible based on the capacity of surviving tubular cells to dedifferentiate and replace lost cells via cell division. Here we show by tracking individual tubular cells in conditional Pax8/Confetti mice that kidney function is recovered after AKI despite substantial tubular cell loss. Cell cycle and ploidy analysis upon AKI in conditional Pax8/FUCCI2aR mice and human biopsies identify endocycle-mediated hypertrophy of tubular cells. By contrast, a small subset of Pax2+ tubular progenitors enriches via higher stress resistance and clonal expansion and regenerates necrotic tubule segments, a process that can be enhanced by suitable drugs. Thus, renal functional recovery upon AKI involves remnant tubular cell hypertrophy via endocycle and limited progenitor-driven regeneration that can be pharmacologically enhanced.
- Published
- 2018
- Full Text
- View/download PDF
41. The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis.
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Palazzo V, Provenzano A, Becherucci F, Sansavini G, Mazzinghi B, Orlandini V, Giunti L, Roperto RM, Pantaleo M, Artuso R, Andreucci E, Bargiacchi S, Traficante G, Stagi S, Murer L, Benetti E, Emma F, Giordano M, Rivieri F, Colussi G, Penco S, Manfredini E, Caruso MR, Garavelli L, Andrulli S, Vergine G, Miglietti N, Mancini E, Malaventura C, Percesepe A, Grosso E, Materassi M, Romagnani P, and Giglio S
- Subjects
- Adolescent, Adult, Child, Child, Preschool, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Testing, Genotype, Hearing Loss, Sensorineural genetics, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Middle Aged, Mutation, Phenotype, Retrospective Studies, Young Adult, Acidosis, Renal Tubular genetics, Anion Exchange Protein 1, Erythrocyte genetics, Rare Diseases genetics, Renal Insufficiency, Chronic genetics, Vacuolar Proton-Translocating ATPases genetics
- Abstract
Primary distal renal tubular acidosis is a rare genetic disease. Mutations in SLC4A1, ATP6V0A4, and ATP6V1B1 genes have been described as the cause of the disease, transmitted as either an autosomal dominant or recessive trait. Particular clinical features, such as sensorineural hearing loss, have been mainly described in association with mutations in one gene instead of the others. Nevertheless, the diagnosis of distal renal tubular acidosis is essentially based on clinical and laboratory findings, and the series of patients described so far are usually represented by small cohorts. Therefore, a strict genotype-phenotype correlation is still lacking, and questions about whether clinical and laboratory data should direct the genetic analysis remain open. Here, we applied next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype. A genetic cause was determined in 71.9% of cases. In our group of sporadic cases, clinical features, including sensorineural hearing loss, are not specific indicators of the causal underlying gene. Mutations in the ATP6V0A4 gene are quite as frequent as mutations in ATP6V1B1 in patients with recessive disease. Chronic kidney disease was frequent in patients with a long history of the disease. Thus, our results suggest that when distal renal tubular acidosis is suspected, complete genetic testing could be considered, irrespective of the clinical phenotype of the patient., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
42. Biologic modulation in renal regeneration.
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Mazzinghi B, Romagnani P, and Lazzeri E
- Abstract
Introduction: Chronic kidney disease (CKD) is recognized as a health care problem of increasing importance. Following the discovery of renal progenitors, the investigation of new therapeutic approaches to promote the kidney regenerative capacity has received increasing research attention., Areas Covered: The authors discuss the current knowledge of glomerular regeneration by renal progenitors and the modulation of their behavior through chemical and biological agents. The regenerative capacity of renal progenitors after injury must be regulated in order to prevent an inefficient or excessive response that could lead to a failed attempt to replace lost podocytes. In addition, they discuss the most relevant pathways involved in tubular repair and how these could be modulated in order to obtain renal regeneration rather than progression of a fibrotic maladaptive response., Expert Opinion: Modulation of the endogenous renal regenerative capacity is a new approach in the treatment of kidney diseases. Research efforts that concentrate on the potential regenerative capacity of the kidney can be advantageous when the experimental results are translated into clinical practice and may open the way to new therapeutic strategies for CKD.
- Published
- 2016
- Full Text
- View/download PDF
43. Next generation sequencing and functional analysis of patient urine renal progenitor-derived podocytes to unravel the diagnosis underlying refractory lupus nephritis.
- Author
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Romagnani P, Giglio S, Angelotti ML, Provenzano A, Becherucci F, Mazzinghi B, Müller S, Amann K, Weidenbusch M, Romoli S, Lazzeri E, and Anders HJ
- Subjects
- Adolescent, Female, Humans, Lupus Nephritis etiology, Podocytes pathology, Recurrence, Stem Cells pathology, High-Throughput Nucleotide Sequencing methods, Kidney physiopathology, Lupus Nephritis diagnosis, Lupus Nephritis urine, Podocytes metabolism, Stem Cells metabolism
- Abstract
Often the cause of refractory lupus nephritis (RLN) remains unclear. We performed next-generation sequencing for podocyte genes in an RLN patient and identified compound heterozygosity for APOL1 risk alleles G1 and G2 and a novel homozygous c.[1049C>T]+[1049C>T] NPHS1 gene variant of unknown significance. To test for causality renal progenitor cells isolated from urine of this patient were differentiated into podocytes in vitro. Podocytes revealed aberrant nephrin trafficking, cytoskeletal structure and lysosomal leakage, and increased detachment as compared with podocytes isolated from controls. Thus, lupus podocytopathy can be confirmed as a cause of RLN by functional genetics on patient-derived podocytes., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
44. Lessons from genetics: is it time to revise the therapeutic approach to children with steroid-resistant nephrotic syndrome?
- Author
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Becherucci F, Mazzinghi B, Provenzano A, Murer L, Giglio S, and Romagnani P
- Subjects
- Child, Child, Preschool, Glucocorticoids therapeutic use, Humans, Immunosuppressive Agents therapeutic use, Nephrotic Syndrome drug therapy, Nephrotic Syndrome genetics, Drug Resistance genetics, Nephrotic Syndrome congenital
- Abstract
Primitive nephrotic syndrome is one of the most common glomerular diseases in childhood and represents the clinical manifestation of various pathologic changes in the kidney. In children, nephrotic syndrome is classified based on the initial response to empiric corticosteroid treatment, which is considered as the best predictor of patients' final outcome. The advent of next-generation sequencing technology showed that genetic alterations in structural genes of the podocyte can be recognized in a significant proportion of not only familial or syndromic patients with steroid-resistant nephrotic syndrome (SRNS), but also of sporadic cases, raising the question of whether it is time to update current protocols of patient care. In this review, we discuss the implications derived from several studies describing a high prevalence in children with SRNS of pathogenic mutations in a group of genes and their unresponsiveness to immunosuppressive therapy. We propose a diagnostic and therapeutic algorithm to reduce the exposure to immunosuppressants in individuals with unresponsive forms of the disease, sparing patients the untoward side effects of prolonged ineffective treatments, and at the same time guaranteeing the optimal immunosuppressive or other new therapy in potentially responsive patients.
- Published
- 2016
- Full Text
- View/download PDF
45. Podocyte Regeneration Driven by Renal Progenitors Determines Glomerular Disease Remission and Can Be Pharmacologically Enhanced.
- Author
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Lasagni L, Angelotti ML, Ronconi E, Lombardi D, Nardi S, Peired A, Becherucci F, Mazzinghi B, Sisti A, Romoli S, Burger A, Schaefer B, Buccoliero A, Lazzeri E, and Romagnani P
- Subjects
- Animals, Cells, Cultured, Glycogen Synthase Kinase 3 antagonists & inhibitors, Indoles pharmacology, Indoles therapeutic use, Mice, Mice, Inbred C57BL, Oximes pharmacology, Oximes therapeutic use, Podocytes drug effects, Podocytes metabolism, Renal Insufficiency, Chronic drug therapy, Stem Cells drug effects, Stem Cells metabolism, Cell Differentiation, Podocytes cytology, Regeneration, Renal Insufficiency, Chronic pathology, Stem Cells cytology
- Abstract
Podocyte loss is a general mechanism of glomerular dysfunction that initiates and drives the progression of chronic kidney disease, which affects 10% of the world population. Here, we evaluate whether the regenerative response to podocyte injury influences chronic kidney disease outcome. In models of focal segmental glomerulosclerosis performed in inducible transgenic mice where podocytes are tagged, remission or progression of disease was determined by the amount of regenerated podocytes. When the same model was established in inducible transgenic mice where renal progenitors are tagged, the disease remitted if renal progenitors successfully differentiated into podocytes, while it persisted if differentiation was ineffective, resulting in glomerulosclerosis. Treatment with BIO, a GSK3s inhibitor, significantly increased disease remission by enhancing renal progenitor sensitivity to the differentiation effect of endogenous retinoic acid. These results establish renal progenitors as critical determinants of glomerular disease outcome and a pharmacological enhancement of their differentiation as a possible therapeutic strategy., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
46. Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders.
- Author
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Lazzeri E, Ronconi E, Angelotti ML, Peired A, Mazzinghi B, Becherucci F, Conti S, Sansavini G, Sisti A, Ravaglia F, Lombardi D, Provenzano A, Manonelles A, Cruzado JM, Giglio S, Roperto RM, Materassi M, Lasagni L, and Romagnani P
- Subjects
- Adolescent, Animals, Case-Control Studies, Child, Child, Preschool, Female, Humans, Infant, Male, Mice, Inbred BALB C, Mice, SCID, Mice, Transgenic, Cell Culture Techniques, Kidney cytology, Kidney Diseases congenital, Stem Cells cytology, Urine cytology
- Abstract
The critical role of genetic and epigenetic factors in the pathogenesis of kidney disorders is gradually becoming clear, and the need for disease models that recapitulate human kidney disorders in a personalized manner is paramount. In this study, we describe a method to select and amplify renal progenitor cultures from the urine of patients with kidney disorders. Urine-derived human renal progenitors exhibited phenotype and functional properties identical to those purified from kidney tissue, including the capacity to differentiate into tubular cells and podocytes, as demonstrated by confocal microscopy, Western blot analysis of podocyte-specific proteins, and scanning electron microscopy. Lineage tracing studies performed with conditional transgenic mice, in which podocytes are irreversibly tagged upon tamoxifen treatment (NPHS2.iCreER;mT/mG), that were subjected to doxorubicin nephropathy demonstrated that renal progenitors are the only urinary cell population that can be amplified in long-term culture. To validate the use of these cells for personalized modeling of kidney disorders, renal progenitors were obtained from (1) the urine of children with nephrotic syndrome and carrying potentially pathogenic mutations in genes encoding for podocyte proteins and (2) the urine of children without genetic alterations, as validated by next-generation sequencing. Renal progenitors obtained from patients carrying pathogenic mutations generated podocytes that exhibited an abnormal cytoskeleton structure and functional abnormalities compared with those obtained from patients with proteinuria but without genetic mutations. The results of this study demonstrate that urine-derived patient-specific renal progenitor cultures may be an innovative research tool for modeling of genetic kidney disorders., (Copyright © 2015 by the American Society of Nephrology.)
- Published
- 2015
- Full Text
- View/download PDF
47. Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression.
- Author
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Giglio S, Provenzano A, Mazzinghi B, Becherucci F, Giunti L, Sansavini G, Ravaglia F, Roperto RM, Farsetti S, Benetti E, Rotondi M, Murer L, Lazzeri E, Lasagni L, Materassi M, and Romagnani P
- Subjects
- Adolescent, Algorithms, Alleles, Animals, Biopsy, Child, Child, Preschool, Female, High-Throughput Nucleotide Sequencing, Humans, Immunosuppression Therapy methods, Infant, Male, Models, Genetic, Mutation, Mutation, Missense, Phenotype, Retrospective Studies, Steroids therapeutic use, Immunosuppressive Agents therapeutic use, Nephrotic Syndrome genetics
- Abstract
In children, sporadic nephrotic syndrome can be related to a genetic cause, but to what extent genetic alterations associate with resistance to immunosuppression is unknown. In this study, we designed a custom array for next-generation sequencing analysis of 19 target genes, reported as possible causes of nephrotic syndrome, in a cohort of 31 children affected by sporadic steroid-resistant nephrotic syndrome and 38 patients who exhibited a similar but steroid-sensitive clinical phenotype. Patients who exhibited extrarenal symptoms, had a familial history of the disease or consanguinity, or had a congenital onset were excluded. We identified a genetic cause in 32.3% of the children with steroid-resistant disease but zero of 38 children with steroid-sensitive disease. Genetic alterations also associated with lack of response to immunosuppressive agents in children with steroid-resistant disease (0% of patients with alterations versus 57.9% of patients without alterations responded to immunosuppressive agents), whereas clinical features, age at onset, and pathologic findings were similar in steroid-resistant patients with and without alterations. These results suggest that heterogeneous genetic alterations in children with sporadic forms of nephrotic syndrome associate with resistance to steroids as well as immunosuppressive treatments. In these patients, a comprehensive screening using such an array may, thus, be useful for genetic counseling and may help clinical decision making in a fast and cost-efficient manner., (Copyright © 2015 by the American Society of Nephrology.)
- Published
- 2015
- Full Text
- View/download PDF
48. Proteinuria impairs podocyte regeneration by sequestering retinoic acid.
- Author
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Peired A, Angelotti ML, Ronconi E, la Marca G, Mazzinghi B, Sisti A, Lombardi D, Giocaliere E, Della Bona M, Villanelli F, Parente E, Ballerini L, Sagrinati C, Wanner N, Huber TB, Liapis H, Lazzeri E, Lasagni L, and Romagnani P
- Subjects
- Albuminuria pathology, Animals, Cells, Cultured, Female, Glomerulosclerosis, Focal Segmental etiology, Humans, Mice, Mice, SCID, Response Elements physiology, Tretinoin pharmacology, Albuminuria complications, Podocytes physiology, Regeneration, Tretinoin metabolism
- Abstract
In CKD, the risk of kidney failure and death depends on the severity of proteinuria, which correlates with the extent of podocyte loss and glomerular scarring. We investigated whether proteinuria contributes directly to progressive glomerulosclerosis through the suppression of podocyte regeneration and found that individual components of proteinuria exert distinct effects on renal progenitor survival and differentiation toward a podocyte lineage. In particular, albumin prevented podocyte differentiation from human renal progenitors in vitro by sequestering retinoic acid, thus impairing retinoic acid response element (RARE)-mediated transcription of podocyte-specific genes. In mice with Adriamycin nephropathy, a model of human FSGS, blocking endogenous retinoic acid synthesis increased proteinuria and exacerbated glomerulosclerosis. This effect was related to a reduction in podocyte number, as validated through genetic podocyte labeling in NPHS2.Cre;mT/mG transgenic mice. In RARE-lacZ transgenic mice, albuminuria reduced retinoic acid bioavailability and impaired RARE activation in renal progenitors, inhibiting their differentiation into podocytes. Treatment with retinoic acid restored RARE activity and induced the expression of podocyte markers in renal progenitors, decreasing proteinuria and increasing podocyte number, as demonstrated in serial biopsy specimens. These results suggest that albumin loss through the damaged filtration barrier impairs podocyte regeneration by sequestering retinoic acid and promotes the generation of FSGS lesions. Our findings may explain why reducing proteinuria delays CKD progression and provide a biologic rationale for the clinical use of pharmacologic modulators to induce regression of glomerular diseases.
- Published
- 2013
- Full Text
- View/download PDF
49. [Tubular progenitor cells: new protagonists of tubular regeneration].
- Author
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Angelotti ML, Ronconi E, Peired A, Mazzinghi B, Lazzeri E, Lasagni L, and Romagnani P
- Subjects
- AC133 Antigen, Animals, Antigens, CD physiology, CD24 Antigen physiology, Glycoproteins physiology, Humans, Peptides physiology, Vascular Cell Adhesion Molecule-1 physiology, Kidney Tubules physiology, Regeneration, Stem Cells physiology
- Published
- 2012
50. MicroRNA-324-3p promotes renal fibrosis and is a target of ACE inhibition.
- Author
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Macconi D, Tomasoni S, Romagnani P, Trionfini P, Sangalli F, Mazzinghi B, Rizzo P, Lazzeri E, Abbate M, Remuzzi G, and Benigni A
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Disease Progression, Endopeptidases metabolism, Fibrosis, In Vitro Techniques, Kidney Diseases metabolism, Kidney Diseases pathology, Kidney Glomerulus metabolism, Kidney Glomerulus pathology, Kidney Tubules metabolism, Kidney Tubules pathology, Male, Rats, Rats, Wistar, Up-Regulation, Angiotensin-Converting Enzyme Inhibitors pharmacology, Kidney metabolism, Kidney pathology, MicroRNAs metabolism, Peptidyl-Dipeptidase A drug effects, Peptidyl-Dipeptidase A metabolism
- Abstract
The contribution of microRNA (miRNA) to the pathogenesis of renal fibrosis is not well understood. Here, we investigated whether miRNA modulates the fibrotic process in Munich Wistar Fromter (MWF) rats, which develop spontaneous progressive nephropathy. We analyzed the expression profile of miRNA in microdissected glomeruli and found that miR-324-3p was the most upregulated. In situ hybridization localized miR-324-3p to glomerular podocytes, parietal cells of Bowman's capsule, and most abundantly, cortical tubules. A predicted target of miR-324-3p is prolyl endopeptidase (Prep), a serine peptidase involved in the metabolism of angiotensins and the synthesis of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). In cultured tubular cells, transient transfection with a miR-324-3p mimic reduced Prep protein and activity, validating Prep as a target of this miRNA. In MWF rats, upregulation of miR-324-3p associated with markedly reduced expression of Prep in both glomeruli and tubules, low urine Ac-SDKP, and increased deposition of collagen. ACE inhibition downregulated glomerular and tubular miR-324-3p, promoted renal Prep expression, increased plasma and urine Ac-SDKP, and attenuated renal fibrosis. In summary, these results suggest that dysregulation of the miR-324-3p/Prep pathway contributes to the development of fibrosis in progressive nephropathy. The renoprotective effects of ACE inhibitors may result, in part, from modulation of this pathway, suggesting that it may hold other potential therapeutic targets.
- Published
- 2012
- Full Text
- View/download PDF
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