Angiotensin II Contributes to Podocyte Injury by Increasing TRPC6 Expression via an NFAT-Mediated Positive Feedback Signaling Pathway

• Published in: The American journal of pathology Vol. 179; no. 4; pp. 1719 - 1732
• Main Authors: Nijenhuis, Tom, Sloan, Alexis J, Hoenderop, Joost G.J, Flesche, Jan, van Goor, Harry, Kistler, Andreas D, Bakker, Marinka, Bindels, Rene J.M, de Boer, Rudolf A, Möller, Clemens C, Hamming, Inge, Navis, Gerjan, Wetzels, Jack F.M, Berden, Jo H.M, Reiser, Jochen, Faul, Christian, van der Vlag, Johan
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.10.2011; American Society for Investigative Pathology
• Subjects: Angiotensin II - pharmacology; Angiotensin Receptor Antagonists - pharmacology; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Biological and medical sciences; Calcineurin - metabolism; Calcium - metabolism; Doxorubicin; Feedback, Physiological - drug effects; Gene Expression Regulation - drug effects; HEK293 Cells; Humans; Investigative techniques, diagnostic techniques (general aspects); Kidney Diseases - chemically induced; Kidney Diseases - complications; Kidney Diseases - metabolism; Kidney Diseases - pathology; Medical sciences; Mice; Models, Biological; NFATC Transcription Factors - metabolism; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Podocytes - drug effects; Podocytes - metabolism; Podocytes - pathology; Proteinuria - complications; Proteinuria - metabolism; Proteinuria - pathology; Rats; Regular; Renin - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; TRPC Cation Channels - genetics; TRPC Cation Channels - metabolism; Podocyte; Renin angiotensin system; Anatomic pathology; Signaling pathway; Feedback; Transcription factor NFAT; Lesion; Angiotensin II; TRPC6 gene
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2011.06.033

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 Ca2+ influx and the activation of the Ca2+ -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.