Progressive Glomerulosclerosis Research Articles

X-linked Alport syndrome presenting in mother and son with the same unique histopathological features.

Alport syndrome has been linked to three different genes, that is, COL4A3, COL4A4 and COL4A5. It is characterized by progressive and non-specific glomerulosclerosis with irregular thickening of the glomerular basement membrane (GBM). At times, the histopathologic picture is dominated by lesions that are consistent with focal and segmental glomerulosclerosis or IgA nephropathy. Here, we report the cases of two related individuals (mother and son) who were diagnosed with COL4A5-related Alport syndrome due to a missense variant (p.Gly1170Ser) in a G-X-Y repeat and found to present the same highly unusual histopathological abnormalities on their kidney biopsies. One of the abnormalities shared, which does not appear to have been reported, was reduced COL4A5 immunolabeling that was limited to Bowman's capsule even though the ultrastructure of the GBM was distorted. The other abnormality was superimposed segmental IgA deposition in both individuals, accompanied by mesangial changes in the mother. We feel that these findings provide novel insight into the mechanisms of disease manifestation in Alport syndrome. They suggest, in particular, that collagen expression and/or assemblies in Bowman's capsule is more vulnerable to missense mutations in COL4A5 than elsewhere in the kidney. Our findings also suggest that certain coinherited gene polymorphisms act as unexpectedly important phenotypic determinants in COL4A-related disorders.

Evaluation of glomerular sirtuin-1 and claudin-1 in the pathophysiology of nondiabetic focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome, which is characterized by podocyte injury. Given that the pathophysiology of nondiabetic glomerulosclerosis is poorly understood and targeted therapies to prevent glomerular disease are lacking, we decided to investigate the tight junction protein claudin-1 and the histone deacetylase sirtuin-1 (SIRT1), which are known to be involved in podocyte injury. For this purpose, we first examined SIRT1, claudin-1 and podocin expression in kidney biopsies from patients diagnosed with nondiabetic FSGS and found that upregulation of glomerular claudin-1 accompanies a significant reduction in glomerular SIRT1 and podocin levels. From this, we investigated whether a small molecule activator of SIRT1, SRT1720, could delay the onset of FSGS in an animal model of adriamycin (ADR)-induced nephropathy; 14 days of treatment with SRT1720 attenuated glomerulosclerosis progression and albuminuria, prevented transcription factor Wilms tumor 1 (WT1) downregulation and increased glomerular claudin-1 in the ADR + SRT1720 group. Thus, we evaluated the effect of ADR and/or SRT1720 in cultured mouse podocytes. The results showed that ADR [1 µM] triggered an increase in claudin-1 expression after 30 min, and this effect was attenuated by pretreatment of podocytes with SRT1720 [5 µM]. ADR [1 µM] also led to changes in the localization of SIRT1 and claudin-1 in these cells, which could be associated with podocyte injury. Although the use of specific agonists such as SRT1720 presents some benefits in glomerular function, their underlying mechanisms still need to be further explored for therapeutic use. Taken together, our data indicate that SIRT1 and claudin-1 are relevant for the pathophysiology of nondiabetic FSGS.

A Study of Dyslipidemia and Its Clinical Implications in Childhood Nephrotic Syndrome.

Nephrotic syndrome in children is characterized by dyslipidemia, which is an indirect risk factor for cardiovascular diseases, progressive glomerulosclerosis, and related complications. The objective is to determine the range of lipid profile abnormalities in relation to onset, relapse, and remission, as well as to determine if there is any relationship between dyslipidemia and the frequency of relapses. One hundred and two diagnosed cases of nephrotic syndrome in the age group of less than 12 years were included, out of which 64 patients belonged to the first episode of nephrotic syndrome and 38 patients were relapse cases. Steroid-resistant nephrotic syndrome cases or patients with a history of diabetes mellitus, hypothyroidism, familial hypercholesterolemia, children with chronic kidney disease, and edema due to other causes were excluded from the study. There was a statistically significant increase in lipid parameters except for high-density lipoprotein (HDL) cholesterol at the disease onset when compared to remission in cases of the first episode as well as relapse cases of nephrotic syndrome. There was a positive correlation between relapse frequency and dyslipidemia. Dyslipidaemia was also associated with low serum albumin, with a p-value <0.001, which is statistically significant. Dyslipidemia is significantly higher in relapse cases of nephrotic syndrome and remains higher even during remission. Dyslipidemia is a directly associated risk factor for atherosclerosis and coronary heart disease (CAD), along with progressive glomerulosclerosis. Early identification and treatment of hyperlipidemia is therefore justified so that along with longevity, we can also improve the quality of life of children suffering from nephrotic syndrome.

Nephrotic syndrome: pathophysiology and consequences.

In patients with kidney disease, nephrotic syndrome can lead to several complications including progressive kidney dysfunction. Proteinuria may lead to the formation of cellular or fibrous crescents with reciprocal development of rapidly progressive glomerulonephritis or focal glomerulosclerosis. Proteinuria may also cause overload and dysfunction of tubular epithelial cells, eventually resulting in tubular atrophy and interstitial fibrosis. Hypoalbuminemia is usually associated with increased risk of mortality and kidney dysfunction. Dyslipidemia may increase the risk of atherosclerotic complications, cause podocyte dysfunction and contribute to vascular thrombosis. Urinary loss of anticoagulants and overproduction of coagulation factors may facilitate a hypercoagulable state. Edema, hypogammaglobulinemia, loss of complement factors, and immunosuppressive therapy can favor infection. Treatment of these complications may reduce their impact on the severity of NS. Nephrotic syndrome is a kidney disorder that can worsen the quality of life and increase the risk of kidney disease progression.

Development of angiogenic periglomerular microvessels after acute glomerular lesions in IgA nephropathy.

To clarify the clinicopathological characteristics and role of periglomerular angiogenesis in IgA nephropathy. The renal biopsy specimens of 114 patients with IgA nephropathy were examined. Among them, 46 (40%) showed periglomerular angiogenesis around the glomeruli. CD34 and α-smooth muscle actin (α-SMA) staining in serial sections revealed that these vessels contained CD34+ α-SMA+ microarterioles along with CD34+ α-SMA- capillaries. We termed these "periglomerular microvessels (PGMVs)". Patients with PGMVs (PGMV group) had clinically and histologically more severe disease than those without PGMVs (non-PGMV group) at the time of biopsy. Even after adjusting for age, there were significant differences in the degree of proteinuria and estimated glomerular filtration rate reduction between the PGMV and non-PGMV groups. The PGMV group showed a higher incidence of segmental and global glomerulosclerosis and crescentic lesions than the non-PGMV group (P < 0.01). Here, PGMVs were undetectable in the acute and active inflammation phase, but were observed in the acute to chronic or chronic glomerular remodelling phase. PGMVs mainly developed around glomerular adherent lesions to the Bowman's capsule with small or minimal glomerular sclerotic lesions. Conversely, they were rarely observed in segmental sclerosis areas. The PGMV group is clinically and pathologically more severe than the non-PGMV group; however, they were undetectable in segmental sclerosis with mesangial matrix accumulation. PGMVs might occur after acute/active glomerular lesions, suggesting that PGMVs may inhibit segmental glomerulosclerosis progression and could be a marker for good repair response after acute/active glomerular injury in severe IgA nephropathy cases.

L-Carnitine and Chronic Kidney Disease: A Comprehensive Review on Nutrition and Health Perspectives

Progressive segmental glomerulosclerosis is acknowledged as a characteristic of Chronic Kidney Disease (CKD). It is a major health issue that exponentially reduces health and economy and also causes serious morbidity and mortality across the globe. This review is aimed at comprehending the health perspectives of L-Carnitine (LC) as an adjuvant regimen for alleviating CKD and its associated complications. The data were gathered from different online databases such as Science Direct, Google Scholar, ACS publication, PubMed, Springer, etc., using keywords such as CKD/Kidney disease, current epidemiology and its prevalence, LC supplementations, sources of LC, anti-oxidant and anti-inflammatory potential of LC and its supplementation for mimicking the CKD and its associated problem, etc. Various items of literature concerning CKD were gathered and screened by experts based on their inclusion and exclusion criteria. The findings suggest that, among the different comorbidities such as oxidative stress and inflammatory stress, erythropoietin-resistant anemia, intradialytic hypotension, muscle weakness, myalgia, etc., are considered as the most significant onset symptoms in CKD or hemodialysis patients. LC or creatine supplementation provides an effective adjuvant or therapeutic regimen that significantly reduces oxidative and inflammatory stress and erythropoietin-resistant anemia and evades comorbidities such as tiredness, impaired cognition, muscle weakness, myalgia, and muscle wasting. However, no significant changes were found in biochemical alteration such as creatinine, uric acid, urea, etc., after creatine supplementation in a patient with renal dysfunction. The expert-recommended dose of LC or creatine to a patient is approached for better outcomes of LC as a nutritional therapy regimen for CKD-associated complications. Hence, it can be suggested that LC provides an effective nutritional therapy to ameliorate impaired biochemicals and kidney function and to treat CKD and its associated complications.

Nuclear IL-33 in Fibroblasts Promotes Skin Fibrosis

Systemic sclerosis (SSc) is a complex and poorly understood connective tissue disease characterized by diffuse fibrosis in several organs, especially the skin ( Asano, 2017 Asano Y. Recent advances in the treatment of skin involvement in systemic sclerosis. Inflamm Regen. 2017; 37: 12 Crossref Scopus (6) Google Scholar , Bhattacharyya et al., 2012 Bhattacharyya S. Wei J. Tourtellotte W.G. Hinchcliff M. Gottardi C.G. Varga J. Fibrosis in systemic sclerosis: common and unique pathobiology. Fibrogenesis Tissue Repair. 2012; 5: S18 Crossref Scopus (30) Google Scholar , Denton et al., 2006 Denton C.P. Black C.M. Abraham D.J. Mechanisms and consequences of fibrosis in systemic sclerosis. Nat Clin Pract Rheumatol. 2006; 2: 134-144 Crossref Scopus (156) Google Scholar ). Interleukin (IL)-33 is found to regulate tissue fibrosis in multiple organs ( Kotsiou et al., 2018 Kotsiou O.S. Gourgoulianis K.I. Zarogiannis S.G. IL-33/ST2 Axis in Organ Fibrosis. Frontiers in immunology. 2018; 9: 2432 Crossref PubMed Scopus (96) Google Scholar , Xu et al., 2016 Xu J. Zheng J. Song P. Zhou Y. Guan S. IL33/ST2 pathway in a bleomycininduced pulmonary fibrosis model. Mol Med Rep. 2016; 14: 1704-1708 Crossref Scopus (13) Google Scholar ). However, the exact role of IL-33 in fibrosis remains controversial ( Kotsiou et al., 2018 Kotsiou O.S. Gourgoulianis K.I. Zarogiannis S.G. IL-33/ST2 Axis in Organ Fibrosis. Frontiers in immunology. 2018; 9: 2432 Crossref PubMed Scopus (96) Google Scholar ). Previous studies have shown a pro-fibrotic role for IL-33 cytokine through its receptor, interleukin-1 receptor-like 1(IL1RL1 or ST2), regulating the secretion of pro-fibrotic cytokine, IL-13, from eosinophils, M2 macrophages and type 2 innate lymphoid cells (ILC2) ( Li et al., 2014 Li D. Guabiraba R. Besnard A.G. Komai-Koma M. Jabir M.S. Zhang L. et al. IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice. The Journal of allergy and clinical immunology. 2014; 134: 1422-1432 e11 Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar , Rankin et al., 2010 Rankin A.L. Mumm J.B. Murphy E. Turner S. Yu N. McClanahan T.K. et al. IL-33 induces IL-13-dependent cutaneous fibrosis. J Immunol. 2010; 184: 1526-1535 Crossref PubMed Scopus (188) Google Scholar , Wu et al., 2018 Wu L. Luo Z. Zheng J. Yao P. Yuan Z. Lv X. et al. IL-33 Can Promote the Process of Pulmonary Fibrosis by Inducing the Imbalance Between MMP-9 and TIMP-1. Inflammation. 2018; 41: 878-885 Crossref PubMed Scopus (30) Google Scholar ). However, IL-33 can also play an anti-fibrotic role through the induction of ILC2 cells and regulatory T cells in several organs including the skin ( Cheon et al., 2022 Cheon S.Y. Park J.H. Ameri A.H. Lee R.T. Nazarian R.M. Demehri S. IL-33/Regulatory T-Cell Axis Suppresses Skin Fibrosis. The Journal of investigative dermatology. 2022; Google Scholar , Garbern et al., 2019 Garbern J.C. Williams J. Kristl A.C. Malick A. Rachmin I. Gaeta B. et al. Dysregulation of IL-33/ST2 signaling and myocardial periarteriolar fibrosis. J Mol Cell Cardiol. 2019; 128: 179-186 Abstract Full Text Full Text PDF Scopus (12) Google Scholar , Riedel et al., 2017 Riedel J.H. Becker M. Kopp K. Duster M. Brix S.R. Meyer-Schwesinger C. et al. IL-33-Mediated Expansion of Type 2 Innate Lymphoid Cells Protects from Progressive Glomerulosclerosis. J Am Soc Nephrol. 2017; 28: 2068-2080 Crossref Scopus (71) Google Scholar ). Thus, it is critical to determine the full spectrum of IL-33 effect in fibrosis to develop optimal therapies for its utilization in the treatment of SSc and other fibrosis-associated diseases.

Low-Dose Erythropoietin Amplifies Beneficial Effects of Angiotensin II Blockade on Glomerulosclerosis

Exogenous erythropoietin (EPO) is used to treat anemia in patients with chronic kidney disease (CKD). Concerns about the possible adverse effect of EPO on the progression of CKD have been raised owing to nonerythroid cell effects. We investigated the effects of low-dose EPO, independent of correcting anemia, on existing glomerulosclerosis. Adult mice underwent 5/6 nephrectomy and were randomized into the following 4 groups at week 8 after surgery: vehicle (VEH), losartan (angiotensin II type 1 receptor blocker [ARB]), darbepoetin-α (DA), or combination (DA+ARB). Four weeks later, mice were euthanized, followed by evaluation of renal structure and function. Glomerular endothelial cells and podocytes were cultured to evaluate the effects of DA on cell migration, apoptosis, and Akt signaling. ARB reduced blood pressure, albuminuria, and the level of serum creatinine and increased hematocrit compared with VEH, whereas low-dose DA only reduced the level of serum creatinine. Combination treatment showed a trend to increase hematocrit and survival compared with ARB alone. Combination treatment but not ARB alone significantly reduced the progression of glomerulosclerosis compared with VEH. Low-dose DA resulted in more preserved glomerular and peritubular capillary endothelial cells with increased p-Akt and even further endothelial cell preservation in combination with ARB. In cultured glomerular endothelial cells, angiotensin II induced more apoptosis, reduced migration, and decreased p-Flk1, a receptor for the proangiogenic vascular endothelial growth factor. DA counteracted these injuries and increased p-Akt, a key factor in angiogenesis and cell survival. DA also protected cultured podocytes against transforming growth factor β–induced apoptosis and synaptopodin loss. Low-dose EPO directly protects glomerular and peritubular endothelial cells via Akt phosphorylation. Therefore, treatment using a combination of low-dose EPO and ARB results in less progression of glomerulosclerosis in an experimental CKD model.

PS-C33-3: THE EFFECT OF AGE AND HYPERTENSION ON PODOMETRICS IN DIFFERENT CORTICAL ZONES OF THE HUMAN KIDNEY

Objective: Podocyte loss and resultant nephron loss are common processes in the progression of glomerulosclerosis and CKD. Aging and hypertension are the main causes of benign nephrosclerosis, which is histologically characterized by concomitant appearances of glomerular collapse and enlargement. Glomerular hypertrophy and glomerulosclerosis often preferentially occur in specific cortical zones of the kidney, possibly due to the difference in kidney artery perfusion. However, it is unknown if podometrics, such as podocyte number per glomerulus, podocyte density and podocyte volume, differ among different cortical zones in the human kidneys. The aim of the present study is to determine the effect of aging and hypertension on podometrics in different cortical zones of the human kidneys. Design and method: Autopsy kidneys from 50 Japanese adults without apparent glomerular disease were cross-sectionally analyzed. Podometrics in different cortical zones (superficial/middle/juxtamedullary) were estimated on a single section using a model-based stereology. Results: Median age was 68 years and median eGFR was 73.5 mL/min/1.73m2. Hypertension was identified in 21 (42%) subjects. While podocyte number per glomerulus was similar in the three zones, superficial glomeruli were the smallest and had the highest podocyte density and smallest podocytes. Increasing age and hypertension were associated with lower podocyte number, with age mostly affecting superficial glomeruli, and hypertension mostly affecting juxtamedullary glomeruli. There was no significant interaction between age and hypertension (Figure). Neither podocyte density, podocyte volume nor volume density of podocytes in glomeruli was associated with age or hypertension. Conclusions: Podometric changes, especially decreased podocyte number per glomerulus, may also contribute to the development and different distribution of glomerular morphological phenotypes in aging and hypertension-related benign nephrosclerosis.

Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis.

Progressive glomerulonephritis (GN) is characterized by an excessive accumulation of extracellular (ECM) proteins, mainly type IV collagen (COLIV), in the glomerulus leading to glomerulosclerosis. The current therapeutic approach to GN is suboptimal. Epigenetic drugs could be novel therapeutic options for human disease. Among these drugs, bromodomain and extra-terminal domain (BET) inhibitors (iBETs) have shown beneficial effects in experimental kidney disease and fibrotic disorders. Sex-determining region Y-box 9 (SOX9) is a transcription factor involved in regulating proliferation, migration, and regeneration, but its role in kidney fibrosis is still unclear. We investigated whether iBETs could regulate ECM accumulation in experimental GN and evaluated the role of SOX9 in this process. For this purpose, we tested the iBET JQ1 in mice with anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS). In NTS-injected mice, JQ1 treatment reduced glomerular ECM deposition, mainly by inhibiting glomerular COLIV accumulation and Col4a3 gene overexpression. Moreover, chromatin immunoprecipitation assays demonstrated that JQ1 inhibited the recruitment and binding of BRD4 to the Col4a3 promoter and reduced its transcription. Active SOX9 was found in the nuclei of glomerular cells of NTS-injured kidneys, mainly in COLIV-stained regions. JQ1 treatment blocked SOX9 nuclear translocation in injured kidneys. Moreover, in vitro JQ1 blocked TGF-β1-induced SOX9 activation and ECM production in cultured mesangial cells. Additionally, SOX9 gene silencing inhibited ECM production, including COLIV production. Our results demonstrated that JQ1 inhibited SOX9/COLIV, to reduce experimental glomerulosclerosis, supporting further research of iBET as a potential therapeutic option in progressive glomerulosclerosis.

Esaxerenone inhibits the macrophage-to-myofibroblast transition through mineralocorticoid receptor/TGF-β1 pathway in mice induced with aldosterone.

Renal fibrosis is the inevitable pathway of the progression of chronic kidney disease to end-stage renal disease, which manifests as progressive glomerulosclerosis and renal interstitial fibrosis. In a previous study, we observed severe interstitial fibrosis in the contralateral kidneys of 6-month unilateral ureteral obstruction (UUO) rats, which was accompanied by increased macrophage infiltration and phenotypic transformation; after eplerenone administration, these effects were reduced. Therefore, we hypothesized that this effect was closely related to mineralocorticoid receptor (MR) activation induced by the increased aldosterone (ALD) level. In this study, we used uninephrectomy plus continuous aldosterone infusion in mice to observe whether aldosterone induced macrophage-to-myofibroblast transition (MMT) and renal fibrosis and investigated the signaling pathways. Notably, aldosterone induced predominantly M1 macrophage-to-myofibroblast transition by activating MR and upregulating TGF-β1 expression, which promoted renal fibrosis. These effects were antagonized by the MR blocker esaxerenone. These findings suggest that targeting the MR/TGF-β1 pathway may be an effective therapeutic strategy for renal fibrosis.

Selonsertib Enhances Kidney Protection Beyond Standard of Care in a Hypertensive, Secondary Glomerulosclerosis CKD Model.

Despite widespread use of renin-aldosterone-angiotensin system inhibitors and the benefits of lowering glomerular pressure in patients with CKD, there remains a major unmet need for therapies targeting underlying causes of CKD progression. Apoptosis signal-regulating kinase 1 (ASK1) promotes apoptosis and glomerulosclerosis, and is implicated in the progression of diabetic kidney disease (DKD), a major cause of CKD. Selonsertib is a selective ASK1 inhibitor currently in clinical development for the treatment of DKD. We examined the added benefits of selonsertib on existing glomerulosclerosis and related molecular pathways in the nondiabetic 5/6 nephrectomy (5/6 Nx) rat model in combination with the angiotensin-converting enzyme inhibitor (ACEI) enalapril. Male Sprague Dawley rats underwent 5/6 Nx with kidney biopsy 8 weeks later for assessment of glomerulosclerosis, and were randomized to four treatment groups with equal glomerulosclerosis: selonsertib, enalapril, combination (selonsertib plus enalapril), and untreated controls. Serum creatinine, systolic BP (SBP), and urinary albumin were measured at intervals. Animals were euthanized at week 12 for histologic, biochemical, and molecular analyses. All rats developed hypertension, albuminuria, and glomerulosclerosis by week 8. Kidney function further declined, and glomerulosclerosis and albuminuria progressively increased in controls from week 8 to 12. Enalapril treatment alone from week 8 to 12 reduced SBP versus controls, decreased albuminuria, and resulted in numerically lower glomerulosclerosis. Selonsertib alone had no effect on SBP but preserved kidney function. Combined treatment significantly reduced glomerulosclerosis, with more regression than either monotherapy. Enalapril treatment resulted in fewer interstitial macrophages, whereas selonsertib treatment reduced apoptosis and podocyte loss. RNA-seq revealed that combined treatment influenced pathways related to extracellular matrix and wound healing. Selonsertib targets a novel, nonhemodynamic pathway in CKD. Our data suggest that ASK1 inhibition, when combined with ACEI, has additive effects to reduce progression of glomerulosclerosis, attenuate kidney function decline, and reduce podocyte loss.

MO228: Clinical Features and Obesity Impact on Chronic Kidney Disease Progression in Patients with Glomerular Diseases

Abstract BACKGROUND AND AIMS The kidney disease secondary to obesity is obesity-related glomerulopathy characterized by the following: glomerulomegalia, progressive glomerulosclerosis, proteinuria and progression of renal failure. The aims of the present study were to evaluate the clinical features and 2 years outcome in obese and non-obese patients with glomerular diseases. METHOD This study included 125 patients with renal biopsy-proven glomerular diseases: minimal change disease, FSGS, IgA nephropathy, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mean age 46.93 ± 15.10 years). There were 63 obese (BMI ≥ 27 kg/m2) and 62 non-obese (BMI &amp;lt;27 kg/m2) patients. The serum concentration of protein, albumin, cholesterol, trygliceride, creatinine and daily proteinuria were measured at the time of kidney biopsy, 6, 12 and 24 months after the biopsy. The estimated glomerular filtration rate (eGFR) was calculated according to the equations: Cockcroft–Gault#(Cockcroft–Gault–BMI &amp;lt; 27 kg/m2 Cockcroft–GaultLBW-BMI ≥27kg/m2) and Chronic Kidney Disease Epidemiology Collaboration Equation (CKD–EPI). RESULTS At the time of kidney biopsy, the obese had significantly lower eGFR calculated by formulas: Cockcroft–Gault# (62.29 ± 27.53 versus 96.30 ± 38.80 mL/min) and CKD–EPI (71.52 ± 31.15 versus 86.36 ± 27.63 mL/min/1.73 m2), significantly higher daily proteinuria (6.11 ± 4.94 versus 4.47 ± 4.95 g/day), creatinine (122.14 ± 87.56 versus 93.66 ± 41.40 μmol/L), trygliceride (2.76 ± 1.39 versus 2.20 ± 1.30 mmol/L) in comparison with non-obese. There was statistically significant difference in eGFR calculated by Cockcroft-Gault# 6 months (t = 5.353, P &amp;lt; .01), 12 (t = 5.234, P &amp;lt; .01) and 24 months (t = 2.329, P &amp;lt; .05) after the kidney biopsy between obese and non-obese. The reduction in eGFR Cockcroft–Gault# after 24 months compared with baseline in obese was 14.7%, in non-obese 13.7% (P &amp;gt; 0.05). After 12 months follow-up significantly higher percentage of non-obese patients reached complete remission (59.4% versus 35.3%) compared with obese (χ2 = 4.548), but after 24 months there were no significant difference. CONCLUSION Obese patients at the time of kidney biopsy, 6, 12 and 24 months later had the significant lower eGFR compared to non-obese. After 24 months follow-up there was no significant difference in percentage of patients with complete remission between two groups, although after 12 months follow-up a significantly smaller number of obese were in complete remission.

Amelioration of Murine Diabetic Nephropathy with a SGLT2 Inhibitor Is Associated with Suppressing Abnormal Expression of Hypoxia-Inducible Factors

Diabetic nephropathy (DN), once manifested, is unlikely to completely recover. Factors that influence DN progression were explored by investigating the process of glomerulosclerosis and interstitial fibrosis and chronological changes in glucose, albuminuria, hyperfiltration, and expressions of sodium-glucose cotransporter 2 (SGLT2) and hypoxia-inducible factors (HIFs) up to 50 weeks in inducible cAMP early repressor transgenic mice, a model of severe DN. Long-term intervention with the SGLT2 inhibitor canagliflozin or islet transplantation or heminephrectomy was used. Inducible cAMP early repressor transgenic mice exhibited progressive diabetic glomerulosclerosis and mild interstitial fibrosis, and expressed extensive HIF-1α and HIF-2α in glomerulus and tubules, with sustained hyperfiltration up to 50 weeks. Canagliflozin ameliorated glomerulosclerosis/interstitial fibrosis gradually and reduced HIF overexpression. Islet-transplanted mice exhibited no amelioration. None of the heminephrectomized diabetic mice survived the hyperfiltration overload, but all of the canagliflozin-treated mice survived with re-expressions of HIF-1α and HIF-2α. These results suggest that persistent glomerular hyperfiltration might initiate glomerular injury, and persistent overexpression of HIFs could promote the development of glomerulosclerosis and interstitial fibrosis. Canagliflozin attenuated both changes. Oxidative stress or hypoxia was undetectable in this model. The abnormal expression of HIF-1α and HIF-2α may be a potential therapeutic target for preventing glomerulosclerosis and interstitial fibrosis.

Rapamycin attenuated podocyte apoptosis via upregulation of nestin in Ang II-induced podocyte injury

BackgroundAngiotensin II (Ang II) contributes to the progression of glomerulosclerosis, mainly by inducing podocyte injury. Convincing evidence indicates that the mTOR inhibitor rapamycin could play a fundamental role in protection against podocyte injury. Nestin, a major cytoskeletal protein, is stably expressed in podocytes and correlates with podocyte damage. The purpose of this study was to investigate the effect of rapamycin on podocyte injury induced by Ang II and to clarify the role and mechanism of nestin in the protective effect of rapamycin of podocyte injury.Methods and resultsWe established an Ang II perfusion animal model, and the effects of rapamycin treatment on podocytes were investigated in vivo. In vitro, podocytes were stimulated with Ang II and rapamycin to observe podocyte injury, and nestin-siRNA was transfected to investigate the underlying mechanisms. We observed that Ang II induced podocyte injury both in vivo and in vitro, whereas rapamycin treatment relieved Ang II-induced podocyte injury. We further found that nestin co-localized with p-mTOR in glomeruli, and the protective effect of rapamycin was reduced by nestin-siRNA in podocytes. Moreover, co-IP indicated the interaction between nestin and p-mTOR, and nestin could affect podocyte injury via the mTOR/P70S6K signaling pathway.ConclusionWe demonstrated that rapamycin attenuated podocyte apoptosis via upregulation of nestin expression through the mTOR/P70S6K signaling pathway in an Ang II-induced podocyte injury.

Molecular and Cellular Mechanisms Underlying the Initiation and Progression of Alport Glomerular Pathology.

Alport syndrome results from a myriad of variants in the COL4A3, COL4A4, or COL4A5 genes that encode type IV (basement membrane) collagens. Unlike type IV collagen α1(IV)2α2(IV)1 heterotrimers, which are ubiquitous in basement membranes, α3/α4/α5 have a limited tissue distribution. The absence of these basement membrane networks causes pathologies in some, but not all these tissues. Primarily the kidney glomerulus, the stria vascularis of the inner ear, the lens, and the retina as well as a rare link with aortic aneurisms. Defects in the glomerular basement membranes results in delayed onset and progressive focal segmental glomerulosclerosis ultimately requiring the patient to undergo dialysis and if accessible, kidney transplant. The lifespan of patients with Alport syndrome is ultimately significantly shortened. This review addresses the consequences of the altered glomerular basement membrane composition in Alport syndrome with specific emphasis on the mechanisms underlying initiation and progression of glomerular pathology.

Revisiting glomerular hyperfiltration and examining the concept of high dietary protein-related nephropathy in athletes and bodybuilders.

High-protein diets (HPDs) are popular but their consequences for kidney health, especially among athletes and bodybuilders who typically maintain a high protein intake for a long time, have not been investigated. This review focused on recent studies of the association of HPD with long-term kidney health and the concept of high dietary protein-related nephropathy. Several long-term observational studies including large populations have reinforced the notion that HPDs are associated with a rapid decline of kidney function. An increase in renal blood flow and glomerular hyperfiltration caused by vasodilation, and increased levels of endocrine and paracrine factors (glucagon, IGF-1, prostanoids, and nitric oxide), facilitates the excretion of protein-derived nitrogenous waste. Inhibition of tubule-glomerular feedback and increased proximal tubular Na+ reabsorption after a HPD augment glomerular hyperfiltration and may trigger synthesis of proinflammatory cytokines and receptor for advanced glycation end-products (RAGE). Focal segmental glomerulosclerosis reported in association with anabolic steroid may indeed be a HPD nephropathy given that HPD results in progressive glomerulosclerosis, especially in remnant glomeruli or in diabetic kidney disease but can happen in any high-risk situation, such as solitary kidney and polycystic kidneys. HPD among athletes and bodybuilders in an extreme way across a long-term period may pose a risk to renal health including high incidence of HPD nephropathy.

Therapeutic potential of pro-resolving mediators in diabetic kidney disease.

Renal microvascular disease associated with diabetes [Diabetic kidney disease - DKD] is the leading cause of chronic kidney disease. In DKD, glomerular basement membrane thickening, mesangial expansion, endothelial dysfunction, podocyte cell loss and renal tubule injury contribute to progressive glomerulosclerosis and tubulointerstitial fibrosis. Chronic inflammation is recognized as a major pathogenic mechanism for DKD, with resident and circulating immune cells interacting with local kidney cell populations to provoke an inflammatory response. The onset of inflammation is driven by the release of well described proinflammatory mediators, and this is typically followed by a resolution phase. Inflammation resolution is achieved through the bioactions of endogenous specialized pro-resolving lipid mediators (SPMs). As our understanding of SPMs advances 'resolution pharmacology' based approaches using these molecules are being explored in DKD.

Critical timing of ACEi initiation prevents compensatory glomerular hypertrophy in the remaining single kidney

Increasing evidence suggests that single in kidney states (e.g., kidney transplantation and living donation) progressive glomerulosclerosis limits kidney lifespan. Modeling shows that post-nephrectomy compensatory glomerular volume (GV) increase drives podocyte depletion and hypertrophic stress resulting in proteinuria and glomerulosclerosis, implying that GV increase could serve as a therapeutic target to prevent progression. In this report we examine how Angiotensin Converting Enzyme inhibition (ACEi), started before uninephrectomy can reduce compensatory GV increase in wild-type Fischer344 rats. An unbiased computer-assisted method was used for morphometric analysis. Urine Insulin-like growth factor-1 (IGF-1), the major diver of body and kidney growth, was used as a readout. In long-term (40-week) studies of uni-nephrectomized versus sham-nephrectomized rats a 2.2-fold increase in GV was associated with reduced podocyte density, increased proteinuria and glomerulosclerosis. Compensatory GV increase was largely prevented by ACEi started a week before but not after uni-nephrectomy with no measurable impact on long-term eGFR. Similarly, in short-term (14-day) studies, ACEi started a week before uni-nephrectomy reduced both GV increase and urine IGF-1 excretion. Thus, timing of ACEi in relation to uni-nephrectomy had significant impact on post-nephrectomy “compensatory” glomerular growth and outcomes that could potentially be used to improve kidney transplantation and live kidney donation outcomes.

Effect of disease progression on the podocyte cell cycle in Alport Syndrome

Progression of glomerulosclerosis is associated with loss of podocytes with subsequent glomerular tuft instability. It is thought that a diminished number of podocytes may be able to preserve tuft stability through cell hypertrophy associated with cell cycle reentry. At the same time, reentry into the cell cycle risks podocyte detachment if podocytes cross the G1/S checkpoint and undergo abortive cytokinesis. In order to study cell cycle dynamics during chronic kidney disease (CKD) development, we used a FUCCI model (fluorescence ubiquitination-based cell cycle indicator) of mice with X-linked Alport Syndrome. This model exhibits progressive CKD and expresses fluorescent reporters of cell cycle stage exclusively in podocytes. With the development of CKD, an increasing fraction of podocytes in vivo were found to be in G1 or later cell cycle stages. Podocytes in G1 and G2 were hypertrophic. Heterozygous female mice, with milder manifestations of CKD, showed G1 fraction numbers intermediate between wild-type and male Alport mice. Proteomic analysis of podocytes in different cell cycle phases showed differences in cytoskeleton reorganization and metabolic processes between G0 and G1 in disease. Additionally, in vitro experiments confirmed that damaged podocytes reentered the cell cycle comparable to podocytes in vivo. Importantly, we confirmed the upregulation of PDlim2, a highly expressed protein in podocytes in G1, in a patient with Alport Syndrome, confirming our proteomics data in the human setting. Thus, our data showed that in the Alport model of progressive CKD, podocyte cell cycle distribution is altered, suggesting that cell cycle manipulation approaches may have a role in the treatment of various progressive glomerular diseases characterized by podocytopenia.