Document Detail

Angiotensin II contributes to podocyte injury by increasing TRPC6 expression via an NFAT-mediated positive feedback signaling pathway.
MedLine Citation:
PMID:  21839714     Owner:  NLM     Status:  MEDLINE    
The transient receptor potential channel C6 (TRPC6) is a slit diaphragm-associated protein in podocytes involved in regulating glomerular filter function. Gain-of-function mutations in TRPC6 cause hereditary focal segmental glomerulosclerosis (FSGS), and several human acquired proteinuric diseases show increased glomerular TRPC6 expression. Angiotensin II (AngII) is a key contributor to glomerular disease and may regulate TRPC6 expression in nonrenal cells. We demonstrate that AngII regulates TRPC6 mRNA and protein levels in cultured podocytes and that AngII infusion enhances glomerular TRPC6 expression in vivo. In animal models for human FSGS (doxorubicin nephropathy) and increased renin-angiotensin system activity (Ren2 transgenic rats), glomerular TRPC6 expression was increased in an AngII-dependent manner. TRPC6 expression correlated with glomerular damage markers and glomerulosclerosis. We show that the regulation of TRPC6 expression by AngII and doxorubicin requires TRPC6-mediated Ca(2+) influx and the activation of the Ca(2+)-dependent protein phosphatase calcineurin and its substrate nuclear factor of activated T cells (NFAT). Accordingly, calcineurin inhibition by cyclosporine decreased TRPC6 expression and reduced proteinuria in doxorubicin nephropathy, whereas podocyte-specific inducible expression of a constitutively active NFAT mutant increased TRPC6 expression and induced severe proteinuria. Our findings demonstrate that the deleterious effects of AngII on podocytes and its pathogenic role in glomerular disease involve enhanced TRPC6 expression via a calcineurin/NFAT positive feedback signaling pathway.
Tom Nijenhuis; Alexis J Sloan; Joost G J Hoenderop; Jan Flesche; Harry van Goor; Andreas D Kistler; Marinka Bakker; Rene J M Bindels; Rudolf A de Boer; Clemens C Möller; Inge Hamming; Gerjan Navis; Jack F M Wetzels; Jo H M Berden; Jochen Reiser; Christian Faul; Johan van der Vlag
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-08-11
Journal Detail:
Title:  The American journal of pathology     Volume:  179     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-09-29     Completed Date:  2012-01-23     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1719-32     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Department of Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
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MeSH Terms
Angiotensin II / pharmacology*
Angiotensin Receptor Antagonists / pharmacology
Angiotensin-Converting Enzyme Inhibitors / pharmacology
Calcineurin / metabolism
Calcium / metabolism
Feedback, Physiological / drug effects*
Gene Expression Regulation / drug effects
HEK293 Cells
Kidney Diseases / chemically induced,  complications,  metabolism,  pathology
Models, Biological
NFATC Transcription Factors / metabolism*
Podocytes / drug effects,  metabolism,  pathology*
Proteinuria / complications,  metabolism,  pathology
RNA, Messenger / genetics,  metabolism
Renin / pharmacology
Signal Transduction / drug effects*
TRPC Cation Channels / genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Angiotensin Receptor Antagonists; 0/Angiotensin-Converting Enzyme Inhibitors; 0/NFATC Transcription Factors; 0/Nfatc1 protein, mouse; 0/RNA, Messenger; 0/TRPC Cation Channels; 0/Trpc6 protein, mouse; 0/Trpc6 protein, rat; 11128-99-7/Angiotensin II; 23214-92-8/Doxorubicin; 7440-70-2/Calcium; EC; EC

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