Glomerular podocytes in kidney health and disease

Assady, Suheir; Benzing, Thomas; Kretzler, Matthias; Skorecki, Karl

doi:10.1016/s0140-6736(18)33000-9

Cited by 22 publications

(21 citation statements)

References 14 publications

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“…The uptitration of ramipril was well tolerated. Dosages were not different between groups (mean 4.4 AE 1.1 mg/m 2 placebo; 4.5 AE 0.9 mg/m 2 ramipril; 4.8 AE 1.0 mg/m 2 in the open arm). Dosages in our normotensive children were very similar to the high dosages reached in the ESCAPE trial with hypertensive children.…”

Section: Study Objectives Target Population and Baseline Characterimentioning

confidence: 91%

“…delaying the progression of renal fibrosis is one of the most urgent goals in renoprotective medicine. 2 The type IV collagen disease Alport syndrome (AS) is the second most common monogenic cause of end-stage renal failure (ESRF), responsible for almost 4% of CKD in adults. [3][4][5][6] AS is caused by variants in the COL4A3, COL4A4, and COL4A5 genes, which encode for the a3, a4, and a5 chains of type IV collagen.…”

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confidence: 99%

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A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport’s syndrome

Groß

Tönshoff

Weber

et al. 2020

Kidney International

101

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Section: Study Objectives Target Population and Baseline Characterimentioning

confidence: 91%

mentioning

confidence: 99%

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport’s syndrome

Groß

Tönshoff

Weber

et al. 2020

Kidney International

101

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“…Podocyte injury is now appreciated to be at the crux of many forms of proteinuric kidney diseases 1 , identi cation of novel pathophysiological pathways and molecules in the podocytes is of priority in preventing glomerular disease progression and providing new opportunities for future treatment. During development, tight junctions (TJs) connect immature podocytes at an early stage and disappear along with the widening of the intercellular spaces and the appearance of slit diaphragm (SDs) 2,3 .…”

Section: Introductionmentioning

confidence: 99%

Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease

Yan¹,

Sun

et al. 2021

Preprint

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Although mature podocytes lack tight junctions (TJs) and form slit diaphragms between opposing foot processes, TJ integral membrane protein CLDN5 is predominantly expressed throughout the plasma membrane of podocytes under normal conditions. Here using podocyte specific Cldn5 knockout mice as a model, we identify CLDN5 as a crucial regulator of podocyte function and reveal Cldn5 deletion exacerbates podocyte injury and proteinuria in diabetic nephropathy (DN) mouse model. Mechanistically, CLDN5 absence reduces ZO1 expression and induces the nuclear translocation of ZONAB, followed by transcriptional downregulation of WIF1, which leads to activation of WNT signaling pathway. Knockout Wif1 in podocytes result in the development of proteinuria and typical glomerular ultrastructure change occurring in Cldn5 knockout mice, while targeted delivery of Wif1 to podocytes prevents the development of glomerular nephropathy in Cldn5 knockout diabetic mice. Podocyte-derived WIF1 also plays a paracrine role on tubular epithelial cells, evidenced by animals with podocyte deletion of Cldn5 or Wif1 have worse kidney fibrosis after unilateral ureteral obstruction when compared with littermate controls with intact podocyte WIF1 expression. These findings establish a novel function of podocyte CLDN5 in restricting WNT activity in the kidney.

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“…Proteinuria is a common feature of nephrotic syndrome. Podocyte injury was reported to play a core role in the occurrence of proteinuria [1,2]. Sustained podocyte damage will lead to the disorganization of the cytoskeleton, foot process fusion, and subsequently the emergence of proteinuria.…”

Section: Introductionmentioning

confidence: 99%

Calcineurin inhibitors ameliorate PAN‐induced podocyte injury through the NFAT–Angptl4 pathway

Shen

Zhang

Lin

et al. 2020

The Journal of Pathology

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Podocyte injury plays a vital role in proteinuria and nephrotic syndrome. Calcineurin (CaN) inhibitors are effective in reducing proteinuria. However, their molecular mechanism is still not fully understood. Angiopoietin-like-4 (ANGPTL4) is a secreted protein that mediates proteinuria in podocyte-related nephropathy. In this study, we established a puromycin aminonucleoside (PAN)-induced minimal-change disease (MCD) rat model and a cultured podocyte injury model. We found that CaN inhibitors protected against PAN-induced podocyte injury, accompanied by an inhibition of Nfatc1 and Angptl4 both in vivo and in vitro. Nfatc1 overexpression and knockdown experiments indicated that Angptl4 was regulated by Nfatc1 in podocytes. ChIP assays further demonstrated that Nfatc1 increased Angptl4 expression by binding to the Angptl4 promoter. In addition, overexpression and knockdown of Angptl4 revealed that Angptl4 directly induced rearrangement of the cytoskeleton of podocytes, reduced the expression of synaptopodin, and enhanced PAN-induced podocyte apoptosis. Furthermore, in a cohort of 83 MCD and 94 membranous nephropathy (MN) patients, we found increased expression of serum ANGPTL4 compared to 120 healthy controls, and there were close correlations between serum ANGPTL4 and Alb, urinary protein, urinary Alb, eGFR, Scr, and BUN in MCD patients. No obvious correlation was found in MN patients. Immunofluorescence studies indicated that increased ANGPTL4 in MCD and MN patients was located mostly in podocytes. In conclusion, our results demonstrate that CaN inhibitors ameliorate PAN-induced podocyte injury by targeting Angptl4 through the NFAT pathway, and Angptl4 plays a vital role in podocyte injury and is involved in human podocyte-related nephropathy.

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Glomerular podocytes in kidney health and disease

Cited by 22 publications

References 14 publications

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport’s syndrome

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport’s syndrome

Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease

Calcineurin inhibitors ameliorate PAN‐induced podocyte injury through the NFAT–Angptl4 pathway

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