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Background: C4d may be used as a marker to evaluate the condition and prognosis of adults with IgA nephropathy, but there have been few studies of children with IgA nephropathy. Methods: C4d immunohistochemical staining was performed on samples from children with IgA nephropathy with C1q-negative immunofluorescence. The clinical and pathological treatment and prognostic characteristics of children in the C4d-positive and -negative groups were compared. Results: A total of sixty-five children with IgA nephropathy were included in the study and were followed up for an average of 37 months. C4d was mainly deposited along the capillary loops. The urinary protein-to-creatinine ratio (UPCR) in the C4d-positive group was significantly higher than that in the C4d-negative group (3.97 vs. 0.81, P < 0.001), and the average integrated optical density value of each child was positively correlated with the UPCR (r = 0.441, P < 0.001). There was a significant difference in the proportions of children with mesangial hypercellularity (M1) (68.97% vs. 44.44%, P = 0.048) and segmental glomerulosclerosis (S1) (65.52% vs. 33.33%, P = 0.010) between the C4d-positive group and the C4d-negative group. The proportion of children who received immunosuppressants in the C4d-positive group was higher than that in the C4d-negative group (86.21% vs. 36.11%, P < 0.001). There was no significant difference in the proportion of children developing kidney failure between the two groups. Conclusion: C4d was found to be associated with proteinuria, segmental lesions, and immunosuppressant treatment. Activation of the lectin pathway may reflect the severity of clinical and pathological manifestations of IgA nephropathy in children. [ABSTRACT FROM AUTHOR]

Childhood-onset systemic lupus erythematosus (SLE) is characterized by increased rates of kidney involvement, termed lupus nephritis. Despite the significant morbidity and mortality associated with this disease, lupus nephritis trials have been plagued by repeated failures to meet clinical endpoints. However, improvements in trial design and the development of targeted approaches have begun to yield promising results, including two new FDA-approved lupus nephritis treatments since 2020. These include belimumab, a monoclonal antibody targeting the B cell survival cytokine BAFF (B cell activating factor), and voclosporin, a cyclosporin analog with improved pharmacokinetic characteristics. In this review, we will summarize the data supporting regulatory approval for these agents in lupus nephritis and highlight ongoing clinical trials targeting the diverse immunologic drivers of renal inflammation in SLE. While pediatric patients remain underrepresented in lupus clinical trials, given the increased severity of childhood-onset SLE and need for long-term protection from kidney damage, we anticipate the need for off-label use of these targeted therapies in the pediatric population. Future studies are needed to define optimal patient selection, drug combinations, and treatment duration in pediatric lupus nephritis. [ABSTRACT FROM AUTHOR]

Background: Both IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephropathy (HSPN) are characterized by glomerular mesangial IgA deposition. Several large studies on adults have suggested that glomerular C4d deposition has prognostic value in IgAN. However, there are few relevant studies on the clinical value of C4d deposition in children with IgAN or HSPN. Methods: We performed a retrospective cohort study in pediatric patients with IgAN or HSPN. Clinicopathological data were collected at the time of kidney biopsy. Kidney C4d deposition was analyzed by immunohistochemistry. The end point was defined as a ≥ 20% decrease in estimated glomerular filtration from baseline. Results: We enrolled 75 children, including 36 children with IgAN and 39 with HSPN. The prevalence of C4d deposition was 36% (27/75). C4d deposition was more abundant in children with proteinuria ≥ 50 mg/kg/day (51.9% versus 20.8%, P = 0.006) or nephrotic syndrome (37.0% versus 10.4%, P = 0.006). Mesangial hypercellularity (hazard ratio [HR], 5.745, 95% confidence interval [CI], 1.670–19.761, P = 0.006) and IgM deposition (HR, 4.522, 95% CI, 1.321–15.478, P = 0.016) were associated with C4d deposition. After a median follow-up of 22 months, seven (19.4%) IgAN patients and one (2.6%) HSPN patient had decreased kidney function. In children with IgAN, positive C4d was associated with decreased kidney function (P = 0.047). Conclusion: Glomerular C4d deposition was associated with mesangial hypercellularity and glomerular IgM deposition in IgAN and HSPN. Glomerular C4d deposition may be a risk factor for eGFR decline in children with IgAN. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complicated autoimmune disease with female susceptibility. It is characterized by over-activation of the immune system and deposit of autoimmune complex in multiple organs. High heterogeneity, unpredictable disease course of SLE as well as the lack of specific and sensitive biomarkers posed diagnostic challenges to clinicians. Despite the complicated clinical presentation and pathogenesis of SLE, research regarding this disease has made many significant breakthroughs over the past decades. Some new learning can potentially be translated into clinical practice. In addition, new classification criteria to increase diagnostic accuracy were defined in 2019 by the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR). Real-world studies have accumulated evidence for the adoption of this new classification criteria. Abundant classification criteria, improved recognition of organ-specific manifestations, and updated knowledge about lupus autoantibodies enable earlier diagnosis and more personalized medicine. Thus, it is important to update our knowledge about the latest clinical practices for lupus diagnosis. This review provides new insight into the diagnosis of SLE by summarizing recent advances in epidemiology, etiology, classification criteria, clinical manifestations, and study of autoantibodies. [ABSTRACT FROM AUTHOR]

Background: Complement activation has an important role in the pathogenesis of IgA nephropathy. Objective: To determine the correlation between IgAC3 ratio (IgA/C3) and total Oxford score and predictive value of IgA/C3 in IgA nephropathy. Methods Forty-three patients diagnosed with IgA nephropathy with > 10 glomerular + 1 arteries in biopsy were included in the study. Hematological and biochemical variables of the blood sample taken before the biopsy and total Oxford score were recorded. The study group was divided into two groups as proteinuria ≥ 1 g (PU ≥ 1) and proteinuria < 1 g (PU < 1). Statistics were carried out with SPSS 22.0 program. p <.05 considered as significant. Results: The mean age of 43 patients was 40.4 (± 11.9) years; 51.2% of them were women. Proteinuria as 1 g or more was in 27 of 43 patients, and less than 1 g in 16 patients. The serum C3 level was lower in the group with PU ≥ 1 and showed a significant positive correlation with the IgA/C3 total Oxford score. Conclusion: A significant correlation was found between serum IgA/C3 and total Oxford score. [ABSTRACT FROM AUTHOR]

Purpose: To study the effect of SARS-CoV-2 infection on pregnancy rates in frozen embryo transfer (FET) cycles. Methods: A retrospective cohort study including women under the age of 42 with documented SARS-CoV-2 infection up to 1 year prior to treatment, undergoing FET cycles in the first half of 2021, with transfer of embryos generated prior to the infection. Controls were SARS-CoV-2 non-diagnosed, non-vaccinated women matched by age, number, and day of embryo transfer. Demographic and cycle characteristics and outcomes were compared. Results: Forty-one recovered women and 41 controls were included. Pregnancy rates were 29% and 49% respectively (p = 0.070). Stratification by time from SARS-CoV-2 infection to transfer into ≤ 60 and > 60 days revealed a difference in pregnancy rates, with women in the COVID group having lower pregnancy rates if infected in proximity to the transfer (21% vs. 55%; p = 0.006). In a logistic regression model, infection was a significant variable (p = 0.05, OR 0.325, 95% CI 0.106–0.998). Logistic regression applied on the subgroup of women infected in proximity to the transfer further strengthened the univariate results, with COVID-19 remaining a significant parameter (p = 0.005, OR 0.072, 95% CI 0.012–0.450). Conclusions: In FET cycles of patients with past SARS-CoV-2 infection, in which oocytes were retrieved prior to infection, decreased pregnancy rates were observed, specifically in patients who recovered less than 60 days prior to embryo transfer. Pending further studies, in cases of FET cycles with limited number of embryos, postponing embryo transfer for at least 60 days following recovery from COVID-19 might be considered when feasible. [ABSTRACT FROM AUTHOR]

SARS-CoV-2, the virus responsible for COVID-19, uses angiotensin converting enzyme 2 (ACE2) as its primary cell-surface receptor. ACE2 is a key enzyme in the counter-regulatory pathway of the broader renin-angiotensin system (RAS) that has been implicated in a broad array of human pathology. The RAS is composed of two competing pathways that work in opposition to each other: the "conventional" arm involving angiotensin converting enzyme (ACE) generating angiotensin-2 and the more recently identified ACE2 pathway that generates angiotensin (1–7). Following the original SARS pandemic, additional studies suggested that coronaviral binding to ACE2 resulted in downregulation of the membrane-bound enzyme. Given the similarities between the two viruses, many have posited a similar process with SARS-CoV-2. Proponents of this ACE2 deficiency model argue that downregulation of ACE2 limits its enzymatic function, thereby skewing the delicate balance between the two competing arms of the RAS. In this review we critically examine this model. The available data remain incomplete but are consistent with the possibility that the broad multisystem dysfunction of COVID-19 is due in large part to functional ACE2 deficiency leading to angiotensin imbalance with consequent immune dysregulation and endothelial cell dysfunction. [ABSTRACT FROM AUTHOR]

Glomerular diseases are often chronic or recurring and thus associated with a tremendous physical, psychological, and economic burden. Their etiologies are often unknown, and their pathogeneses are frequently poorly understood. The diagnoses and management of these diseases are therefore based on clinical features, traditional laboratory markers, and, often, kidney pathology. However, the clinical presentation can be highly variable, the kidney pathology may not establish a definitive diagnosis, and the therapeutic responses and resulting clinical outcomes are often unpredictable. To try to address these challenges, significant research efforts have been made over the last decade to identify potential biomarkers that can help clinicians optimize the diagnosis and prognosis at clinical presentation, as well as help predict long-term outcomes. Unfortunately, these efforts have to date only identified a single biomarker for glomerular disease that has been fully validated and developed for widespread clinical use (anti-PLA2R antibodies to diagnose membranous nephropathy). In this manuscript, we review the definitions and development of biomarkers, as well as the current knowledge on both historical and novel candidate biomarkers of glomerular disease, with an emphasis on those associated with idiopathic nephrotic syndrome. [ABSTRACT FROM AUTHOR]

The clinical features of the kidney involvement in immunoglobulin A (IgA) vasculitis (IgAVN) differ in children and adults for both clinical presentation and progression. IgAVN in children has mostly a self-limiting course and favorable resolution, while in adults the kidney involvement is frequently severe with unfavorable outcome. However, a subset of children is at risk of progression within the pediatric age or decades later in adulthood, particularly when the diagnosis and a prompt intervention are delayed. Factors predicting progression and outcome in the whole spectrum of age have been investigated in recent research, as well as the relationship between IgAVN and primary IgAN, which share the same pathology features, in the light of peculiar clinical differences and progression tendencies, and hence need for selective treatments. The search for a personalized treatment in children with IgAV and in different ages of life should rely on the identification of different risks for progression. This review will focus on recent studies which contribute to improve our knowledge in this still largely unclear area. [ABSTRACT FROM AUTHOR]

Crescentic glomerulonephritis represents a group of kidney diseases characterized by rapid loss of kidney function and the formation of glomerular crescents. While the role of the immune system has been extensively studied in relation to the development of crescents, recent findings show that parietal epithelial cells play a key role in the pathophysiology of crescent formation, even in the absence of immune modulation. This review highlights our current understanding of parietal epithelial cell biology and the reported physiological and pathological roles that these cells play in glomerular lesion formation, especially in the context of crescentic glomerulonephritis. [ABSTRACT FROM AUTHOR]

Hepatorenal syndrome (HRS) occurs in patients with cirrhosis or fulminant hepatic failure and is a kind of pre-renal failure due to intense reduction of kidney perfusion induced by severe hepatic injury. While other causes of pre-renal acute kidney injury (AKI) respond to fluid infusion, HRS does not. HRS incidence is 5% in children with chronic liver conditions before liver transplantation. Type 1 HRS is an acute and rapidly progressive form that often develops after a precipitating factor, including gastrointestinal bleeding or spontaneous bacterial peritonitis, while type 2 is considered a slowly progressive form of kidney failure that often occurs spontaneously in chronic ascites settings. HRS pathogenesis is multifactorial. Cirrhosis causes portal hypertension; therefore, stasis and release of vasodilator substances occur in the hepatic vascular bed, leading to vasodilatation of splanchnic arteries and systemic hypotension. Many mechanisms seem to work together to cause this imbalance: splanchnic vasodilatation; vasoactive mediators; hyperdynamic circulation states and subsequent cardiac dysfunction; neuro-hormonal mechanisms; changes in sympathetic nervous system, renin-angiotensin system, and vasopressin. In patients with AKI and cirrhosis, fluid expansion therapy needs to be initiated as soon as possible and nephrotoxic drugs discontinued. Once HRS is diagnosed, pharmacological treatment with vasoconstrictors, mainly terlipressin plus albumin, should be initiated. If there is no response, other options can include surgical venous shunts and kidney replacement therapy. In this regard, extracorporeal liver support can be a bridge for liver transplantation, which remains as the ideal treatment. Further studies are necessary to investigate early biomarkers and alternative treatments for HRS. [ABSTRACT FROM AUTHOR]

The last decade was crucial for our understanding of the renin–angiotensin–aldosterone system (RAAS) as a two-axis, counter-regulatory system, divided into the classical axis, formed by angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the angiotensin type 1 receptor (AT1R), and the alternative axis comprising angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor. Breakthrough discoveries also took place, with other RAAS endopeptides being described, including alamandine and angiotensin A. In this review, we characterize the two RAAS axes and the role of their components in pediatric kidney diseases, including childhood hypertension (HTN), pediatric glomerular diseases, congenital abnormalities of the kidney and urinary tract (CAKUT), and chronic kidney disease (CKD). We also present recent findings on potential interactions between the novel coronavirus, SARS-CoV-2, and components of the RAAS, as well as potential implications of coronavirus disease 2019 (COVID-19) for pediatric kidney diseases. [ABSTRACT FROM AUTHOR]

The pathogenesis of Coronavirus disease 2019 (COVID-19) is gradually being comprehended. A high number of thrombotic episodes are reported, along with the mortality benefits of heparin. COVID-19 can be viewed as a prothrombotic disease. We overviewed the available evidence to explore this possibility. We identified various histopathology reports and clinical case series reporting thromboses in COVID-19. Also, multiple coagulation markers support this. COVID-19 can be regarded as a risk factor for thrombosis. Applying the principles of Virchow's triad, we described abnormalities in the vascular endothelium, altered blood flow, and platelet function abnormalities that lead to venous and arterial thromboses in COVID-19. Endothelial dysfunction, activation of the renin-angiotensin-aldosterone system (RAAS) with the release of procoagulant plasminogen activator inhibitor (PAI-1), and hyperimmune response with activated platelets seem to be significant contributors to thrombogenesis in COVID-19. Stratifying risk of COVID-19 thromboses should be based on age, presence of comorbidities, D-dimer, CT scoring, and various blood cell ratios. Isolated heparin therapy may not be sufficient to combat thrombosis in this disease. There is an urgent need to explore newer avenues like activated protein C, PAI-1 antagonists, and tissue plasminogen activators (tPA). These should be augmented with therapies targeting RAAS, antiplatelet drugs, repurposed antiinflammatory, and antirheumatic drugs. Key Points • Venous and arterial thromboses in COVID-19 can be viewed through the prism of Virchow's triad. • Endothelial dysfunction, platelet activation, hyperviscosity, and blood flow abnormalities due to hypoxia, immune reactions, and hypercoagulability lead to thrombogenesis in COVID-19. • There is an urgent need to stratify COVID-19 patients at risk for thrombosis using age, comorbidities, D-dimer, and CT scoring. • Patients with COVID-19 at high risk for thrombosis should be put on high dose heparin therapy. [ABSTRACT FROM AUTHOR]

Background: Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune and multifactorial disease that can affect the renal system. Exposure to air pollution can trigger systemic inflammation in cSLE patients and increase risk of disease activity. We evaluated effects of individual real-time exposure to air pollutants on renal activity in cSLE patients using the Systemic Lupus Erythematosus Disease Activity Index 2000. Methods: Longitudinal panel study of 108 repetitive measures from 9 pediatric lupus patients. Over three consecutive weeks, daily individual levels of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were measured, as well as weekly clinical evaluation and laboratory tests. This was repeated every 10 weeks over a 1-year period. Specific generalized estimating equation models were used to evaluate the impact of these pollutants on risk of nephritis and anti-dsDNA > 20 UI/mL and on 24-h urine protein and serum complement (C3) levels. Results: An interquartile range (IQR) increase of 18.12 μg/m3 in PM2.5 daily concentration was associated with increased risk of nephritis and positive results for anti-dsDNA. Moreover, increase in 24-h urine protein and decrease in C3 serum levels also associated with exposure to pollutants. An IQR increase in PM2.57-day moving average was associated with increased risks of leukocyturia (3.4; 95% CI 2.6:4.3), positive anti-dsDNA (3.1; 95% CI 2.1:4.0), and 36.3-mg increase (95% IC 20.2:52.3) in 24-h urine protein. An IQR increase (63.1 μg/m3) in 7-day cumulative NO2 levels was associated with decreased serum C3 levels. Conclusions: This prospective study suggests exposure to air pollution can trigger renal activity in cSLE patients. [ABSTRACT FROM AUTHOR]

Purpose: To study the retinal and choroidal microvascular parameters in children with nephrotic syndrome (NS). Methods: This is a cross-sectional study. Optical coherence tomography angiography was used to evaluate the changes of retinal and choroidal microvessels in patients with NS. Thirty NS children and 20 normal controls were included in this study. The macular vessel density (VD) of the superficial capillary plexus (SCP), deep capillary plexus (DCP), choroid capillary plexus (CCP), and foveal avascular zone (FAZ) area of the SCP and DCP was quantitatively calculated. Clinical data including serum protein, blood lipid, uric acid, urea, serum creatinine, urinary protein concentration, urinary creatinine, 24-h urine volume, 24-h urinary total protein, 24-h creatinine clearance rate, and urinary albumin to creatinine ratio were collected. Results: The VDs of the DCP and CCP in children with NS were significantly lower than those in controls (59.35 ± 2.45 vs. 61.15 ± 1.53, p = 0.002, 66.34 ± 1.43 vs. 67.16 ± 1.23, p = 0.042, respectively). The VD of the SCP in children with NS had a tendency to decrease compared with that in controls, but there were no significant differences. There were also no significant differences in FAZ area between the two groups. The VD of the SCP was positively correlated with serum total protein (ρ = 0.446, p = 0.014), serum albumin (ρ = 0.431, p = 0.017), and 24-h urine volume (ρ = 0.389, p = 0.034) but negatively correlated with triglyceride (ρ = − 0.450, p = 0.013), low-density lipoprotein cholesterol (ρ = −0.432, p = 0.017), urinary protein concentration (ρ = − 0.606, p < 0.001), and 24-h urinary total protein (ρ = − 0.517, p = 0.004). The VDs of the SCP, DCP, and CCP were negatively correlated with the urinary albumin to creatinine ratio (ρ = − 0.473, p = 0.008, ρ = − 0.438, p = 0.015, ρ = −0.467, p = 0.009, respectively). Conclusions: Retinal and choroidal VDs were decreased in children with NS and paralleled the severity of kidney disease. Optical coherence tomography angiography can be used as a noninvasive method for evaluating renal injury in patients with NS. [ABSTRACT FROM AUTHOR]

The renin-angiotensin-aldosterone system (RAAS) plays a major role in the regulation of blood pressure and homeostasis. Therefore, it is a commonly used target for pharmacotherapy of cardiovascular diseases in adults. However, the efficacy of this pharmacotherapy can only be limitedly derived into children. Comprehensive knowledge of the humoral parameters acting in the paediatric RAAS (e.g. angiotensin I, angiotensin II, angiotensin 1-7, angiotensin III, and angiotensin IV) might facilitate a more effective and rational pharmacotherapy in children. Therefore, this review aims to provide an overview of the maturing RAAS. Out of 925 identified records, 35 publications were classified as relevant. Physiological and pathophysiological concentrations of angiotensin peptides were compiled and categorised according to European Medicines Agency age groups. Age has a major impact on circulating angiotensin I, angiotensin II, and angiotensin 1-7, which is reflected in an age-dependent decrease during childhood. In contrast to data obtained in adults, no gender-related differences in angiotensin levels were identified. The observed increase in peptide concentrations regarding cardiac- and renal-diseased children is influenced by surgical repair, while evidence for a pharmacological impact is conflicting. A comprehensive set of angiotensin I, angiotensin II, and angiotensin 1-7 values from neonates up to adolescents was compiled. Indicating age as a strong effector. However, evidence about potential promising targets of the RAAS like angiotensin III and angiotensin IV is still lacking in children. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme 2 (ACE2) is a protein consisting of two domains, the N-terminus is a carboxypeptidase homologous to ACE and the C-terminus is homologous to collectrin and responsible for the trafficking of the neutral amino acid transporter B(0)AT1 to the plasma membrane of gut epithelial cells. The carboxypeptidase domain not only metabolizes angiotensin II to angiotensin-(1–7), but also other peptide substrates, such as apelin, kinins and morphins. In addition, the collectrin domain regulates the levels of some amino acids in the blood, in particular of tryptophan. Therefore it is of no surprise that animals with genetic alterations in the expression of ACE2 develop a diverse pattern of phenotypes ranging from hypertension, metabolic and behavioural dysfunctions, to impairments in serotonin synthesis and neurogenesis. This review summarizes the phenotypes of such animals with a particular focus on the central nervous system. [ABSTRACT FROM AUTHOR]

IgA nephropathy is an inflammatory renal disease characterised by the deposition of IgA in the glomerular mesangium and is the most commonly reported primary glomerulonephritis worldwide. Thirty to forty percent of patients with the disease develop progressive renal function decline, requiring renal replacement therapy within two decades of diagnosis. Despite this, accurate individual risk stratification at diagnosis and predicting treatment response remains a challenge. Furthermore, there are currently no disease specific treatments currently licensed to treat the condition due to long standing challenges in the nature and prevalence of the disease. Despite this, there have been exciting recent advances in the field that may represent paradigm shifts in the way IgA nephropathy is managed in the near future. In this review, we explore the evidence base informing current approaches to management and explore new strategies and future directions in the diagnosis and management of IgA nephropathy. [ABSTRACT FROM AUTHOR]

Triiodothyronine (T3) and renin-angiotensin system (RAS) are functionally related in cardiovascular system. Recently, in an in vivo myocardial ischemia/reperfusion (I/R) model in rats, we showed that T3 treatment improved the post-ischemic recovery of cardiac function. In the present study, we used the same experimental model of regional I/R, obtained by 30 min occlusion of the left descending coronary artery, followed by 3-days of reperfusion, to investigate the effect of 48-h treatment (started 1 day after ischemia) with 6 µg/kg/day T3 or vehicle. T3 was delivered by constant subcutaneous infusion via miniosmotic pump. In particular, aim of this work is to evaluate the effects of T3 on the gene expression of the main receptors and enzymes involved in the two cardiac arms of RAS in an in vivo rat model of I/R: AT1R-ACE (detrimental arm) and AT2R/MAS1-ACE2 (protective arm). Gene expression was evaluated by Real-Time PCR in infarct zone (Area-At-Risk: AAR) and in tissues distant from ischemic wound (Remote Zone: RZ). Three different rat groups were used: sham-operated; I/R and I/R + T3. Main result of the study is the opposite response of AT1R and AT2R/MAS1 expression to I/R procedure and to T3 administration after I/R in both AAR and RZ. Moreover, T3 significantly increased ACE and ACE2 enzyme expression in AAR and RZ. This study reveals that T3 stimulates the expression of protective genes related to RAS such as AT2R/MAS1-ACE2 mainly in BZ, suggesting that, at least in part, T3 could be involved in the local cardiac ameliorative response to I/R procedure. [ABSTRACT FROM AUTHOR]

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system, is a promising candidate as a treatment for cancer that reflects its anti-proliferative and anti-angiogenic properties. However, the peptide's therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP 3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer. [ABSTRACT FROM AUTHOR]

The influence of intracellular administration of angiotensin (1-7) (Ang 1-7) on the inward calcium current was investigated in myocytes isolated from the left ventricle of Wistar Kyoto rat hearts using the patch-clamp technique. The results indicated: (1) the intracellular administration of Ang (1-7) (100 nM) enhanced the peak inward calcium current ( I); (2) the intracellular administration of A779 (100 nM) which a Mas receptor inhibitor, abolished the effect of Ang (1-7) on the calcium current; (3) the activation of PKA and consequent phosphorylation of calcium channels seems to be the mechanism involved in the increment of calcium current induced by the heptapeptide because the intracellular dialysis of the PKA inhibitor suppressed the effect of the heptapeptide; (4) the effect of Ang (1-7) was not related to its secretion into the extracellular space; (5)intracellular dialysis of Ang II (100 nM) has an opposite effect and reduced the peak I; (6) extracellular administration of Ang II (100 nM) to cells previously dialyzed with Ang (1-7) also reduced the peak I previously enhanced by Ang (1-7); and (7) intracellular Ang (1-7) reduced the heart cell volume. Implications for heart contractility were discussed. [ABSTRACT FROM AUTHOR]

Diabetes mellitus type 2 (DM2) is a disease with increasing importance in modern societies and insufficient treatment options. Pharmacological stimulation of insulin signaling, which is blunted in DM2, is a promising approach to treat this disease. It has been shown that activation of the angiotensin (Ang)-(1-7)/Mas axis of the renin-angiotensin system leads to an improved glucose uptake. In this study, we intended to evaluate, whether this effect could be exploited therapeutically. We first confirmed that Ang-(1-7) improves insulin signaling and glucose uptake in vitro in cultured cardiomyocytes. We then evaluated the therapeutic effect of a newly developed hydro-xypropyl-β-cyclodextrin-based Ang-(1-7) nano-formulation in a novel transgenic rat model of inducible insulin resistance and DM2. The chronic administration of this compound prevented the marked elevation in blood glucose levels in these rats at a dose of 30 μg/kg, reversed the established hyperglycemic state at a dose of 100 μg/kg, and resulted in improved insulin sensitivity, reduced plasma insulin and decreased diabetic nephropathy. In conclusion, an oral Ang-(1-7) formulation reverses hyperglycemia and its consequences in an animal model of DM2 and represents a novel therapeutic option for the treatment of DM2 and other cardio-metabolic diseases. Key message: [ABSTRACT FROM AUTHOR]

Over the past two decades, considerable advances have been made in our understanding of the renin-angiotensin-aldosterone system (RAAS) and its roles in various disease states. In this review, we will discuss the current state of knowledge of the many components of the RAAS, including new data on prorenin and its receptors, and important angiotensin fragments. The roles of these components of the RAAS in the pathogenesis of primary hypertension and the progression of chronic kidney disease (CKD) will also be highlighted. Given the new understanding of the many components and roles of the RAAS, it may be possible to develop improved therapies for hypertension and CKD. [ABSTRACT FROM AUTHOR]

The nonpeptide AVE0991 is expected to be a putative new drug for cardiovascular diseases. However, the mechanisms for the cardioprotective actions of AVE0991 are still not fully understood. We planned to determine whether AVE0991 attenuates the angiotensin II (AngII)-induced myocardial hypertrophy and whether these AVE0991 effects involved transforming growth factor β1 (TGF-β1) and Smad2. A rat model of neonatal myocardial hypertrophy was induced by AngII. The AngII group significantly increased in protein content, surface area, and [3H]leucine incorporation efficiency by cardiomyocytes, compared to those of the control group ( P < 0.01). The AngII group also had elevated TGF-β1 and Smad2 expression ( P < 0.01). These AngII-induced changes were significantly attenuated by AVE0991 in a dose-dependent manner. In our study, these actions of AngII (10−6 mol/l) were significantly inhibited by both concentrations of AVE0991 (10−5 mol/l and 10−7 mol/l). Moreover, the high AVE0991 group had significantly better inhibition of myocardial hypertrophy than the low AVE0991 group. Meanwhile, the beneficial effects of AVE0991 were completely abolished when the cardiomyocytes were pretreated with Ang-(1–7) receptor antagonist A-779 (10−6 mol/l). These results suggested that AVE0991 prevented AngII-inducing myocardial hypertrophy in a dose-dependent fashion, a process that may be associated with the inhibition of TGF-β1/Smad2 signaling. [ABSTRACT FROM AUTHOR]

Angiotensin (Ang) II is not only generated in the circulation by renin and angiotensin-converting enzyme (ACE) but also is produced locally in numerous organs including kidney, vessels, heart, adrenal gland, eye, testis, and brain. Furthermore, widely distributed mast cells have been shown to be a production site. Local Ang II production process is commonly termed the result of a “tissue” renin–angiotensin system (RAS). Because pharmacological experiments do not easily allow targeting of specific tissues, many novel findings about the functional importance of tissue RAS have been collected from transgenic rodent models. These animals either overexpress or lack RAS components in specific tissues and thereby elucidate their local functions. The data to date show that in most tissues local RAS amplify the actions of circulating Ang II with important implications for physiology and pathophysiology of cardiovascular diseases. This review summarizes the recent findings on the importance of tissue RAS in the most relevant cardiovascular organs. [ABSTRACT FROM AUTHOR]

The peptide angiotensin-(1–7) [Ang-(1–7)] is known to enhance water transport in rat inner medullary collecting duct (IMCD). The aim of this study was to determine the mechanism of the Ang-(1–7) effect on osmotic water permeability (Pf). Pf was measured in the normal rat IMCD perfused in vitro in presence of agonists [Ang-(1–7), arginine vasopressin (AVP) and Ang-(3–8)], and antagonists of the angiotensin and the vasopressin cascade. Ang-(1–7), but not Ang-(3–8), increased Pf significantly. The effect of Ang-(1–7) on Pf was abolished by its selective antagonist, A-779, added before or after Ang-(1–7). Prostaglandin E2 and the protein kinase A inhibitor H8 also blocked the Ang-(1–7) effect. Blockade of vasopressin V1 receptors by antagonists did not change the Ang-(1–7) effect, but pre-treatment with a V2 antagonist abolished the effect of Ang-(1–7) on Pf. Similarly, pre-treatment with A-779 inhibited AVP’s effect on Pf. Forskolin-stimulated Pf was blocked both by A-779 and by the V2 antagonist. Finally, Ang-(1–7) increased cAMP levels in fresh IMCD cell suspensions whilst the forskolin-stimulated cAMP synthesis was decreased by A-779 and the V2 antagonist. These data provide evidence that Ang-(1–7) interacts via its receptor with the AVP V2 system through a mechanism involving adenylate-cyclase activation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which focuses on breast cancer.