RT Journal Article
SR Electronic
T1 Sildenafil Prevents Podocyte Injury <em>via</em> PPAR-<em>γ</em>–Mediated TRPC6 Inhibition
JF Journal of the American Society of Nephrology
JO J. Am. Soc. Nephrol.
FD American Society of Nephrology
SP 1491
OP 1505
DO 10.1681/ASN.2015080885
VO 28
IS 5
A1 Sonneveld, Ramon
A1 Hoenderop, Joost G.
A1 Isidori, Andrea M.
A1 Henique, Carole
A1 Dijkman, Henry B.
A1 Berden, Jo H.
A1 Tharaux, Pierre-Louis
A1 van der Vlag, Johan
A1 Nijenhuis, Tom
YR 2017
UL http://jasn.asnjournals.org/content/28/5/1491.abstract
AB Transient receptor potential channel C6 (TRPC6) gain-of-function mutations and increased TRPC6 expression in podocytes induce glomerular injury and proteinuria. Sildenafil reduces TRPC6 expression and activity in nonrenal cell types, although the mechanism is unknown. Peroxisome proliferator–activated receptor γ (PPAR-γ) is a downstream target of sildenafil in the cyclic guanosine monophosphate (cGMP)–activated protein kinase G (PKG) axis. PPAR-γ agonists, like pioglitazone, appear antiproteinuric. We hypothesized that sildenafil inhibits TRPC6 expression in podocytes through PPAR-γ–dependent mechanisms, thereby counteracting podocyte injury and proteinuria. Treatment with sildenafil, the cGMP derivative 8-bromoguanosine 3′,5′-cyclic monophosphate sodium salt (8-Br-cGMP), or pioglitazone dose-dependently downregulated podocyte injury-induced TRPC6 expression in vitro. Knockdown or application of antagonists of PKG or PPAR-γ enhanced TRPC6 expression in podocytes and counteracted effects of sildenafil and 8-Br-cGMP. We observed similar effects on TRPC6 promoter activity and TRPC6–dependent calcium influx. Chromatin immunoprecipitation showed PPAR-γ binding to the TRPC6 promoter. Sildenafil or pioglitazone treatment prevented proteinuria and the increased TRPC6 expression in rats with adriamycin-induced nephropathy and mice with hyperglycemia-induced renal injury. Rats receiving PPAR-γ antagonists displayed proteinuria and increased podocyte TRPC6 expression, as did podocyte-specific PPAR-γ knockout mice, which were more sensitive to adriamycin and not protected by sildenafil. Thus, sildenafil ameliorates podocyte injury and prevents proteinuria through cGMP- and PKG-dependent binding of PPAR-γ to the TRPC6 promoter, which inhibits TRPC6 promoter activity, expression, and activity. Because sildenafil is approved for clinical use, our results suggest that additional clinical study of its antiproteinuric effect in glomerular disease is warranted.