title: Angiotensin II contributes to podocyte injury by increasing TRPC6 expression via an NFAT-mediated positive feedback signaling pathway.
abstract: 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.
authors.affiliation: Department of Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Nijenhuis
authors.forename: Alexis J
authors.initials: AJ
authors.lastname: Sloan
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: Jan
authors.initials: J
authors.lastname: Flesche
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Kistler
authors.forename: Marinka
authors.initials: M
authors.lastname: Bakker
authors.forename: Rene J M
authors.initials: RJ
authors.lastname: Bindels
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Möller
authors.forename: Inge
authors.initials: I
authors.lastname: Hamming
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Jack F M
authors.initials: JF
authors.lastname: Wetzels
authors.forename: Jo H M
authors.initials: JH
authors.lastname: Berden
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004317:Doxorubicin; D025461:Feedback, Physiological / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism*; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011507:Proteinuria / Q000150:complications / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012083:Renin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D012333:RNA, Messenger; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; C492145:Trpc6 protein, rat; D000804:Angiotensin II; D004317:Doxorubicin; D019703:Calcineurin; D012083:Renin; D002118:Calcium