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10.1681/ASN.2015080885 http://scihub22266oqcxt.onion/10.1681/ASN.2015080885 C5407711!5407711!27895156     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       J+Am+Soc+Nephrol 2017 ; 28 (5): 1491-505 Nephropedia Template TP {{tp|p=27895156|t=2017. Sildenafil Prevents Podocyte Injury via PPAR-??Mediated TRPC6 Inhibition |pdf=|usr=}}{{27895156}} gab.com Text Sildenafil Prevents Podocyte Injury via PPAR- Mediated TRPC6 Inhibition JO: J Am Soc Nephrol http://www.kidney.de/pget.php?&tw=1&pmid=27895156 #FOAvip 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 ? (PPAR-?) is a downstream target of sildenafil in the cyclic guanosine monophosphate (cGMP)?activated protein kinase G (PKG) axis. PPAR-? agonists, like pioglitazone, appear antiproteinuric. We hypothesized that sildenafil inhibits TRPC6 expression in podocytes through PPAR-??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-? 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-? 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-? antagonists displayed proteinuria and increased podocyte TRPC6 expression, as did podocyte-specific PPAR-? 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-? 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. Twit Text FOAVip Sildenafil Prevents Podocyte Injury via PPAR- Mediated TRPC6 Inhibition ????J Am Soc Nephrol http://www.kidney.de/pget.php?&tw=1&pmid=27895156 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=27895156 #FOAvip English Wikipedia <ref>{{Cite pmid|27895156}}</ref> Sildenafil Prevents Podocyte Injury via PPAR-??Mediated TRPC6 Inhibition #MMPMID27895156 Sonneveld R; Hoenderop JG; Isidori AM; Henique C; Dijkman HB; Berden JH; Tharaux PL; van der Vlag J; Nijenhuis T J Am Soc Nephrol 2017[May]; 28 (5): 1491-505 PMID27895156show ga 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 ? (PPAR-?) is a downstream target of sildenafil in the cyclic guanosine monophosphate (cGMP)?activated protein kinase G (PKG) axis. PPAR-? agonists, like pioglitazone, appear antiproteinuric. We hypothesized that sildenafil inhibits TRPC6 expression in podocytes through PPAR-??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-? 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-? 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-? antagonists displayed proteinuria and increased podocyte TRPC6 expression, as did podocyte-specific PPAR-? 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-? 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. äSildenafil Prevents Podocyte Injury via PPAR-??Mediated TRPC6 Inhibiti(epmc).pdf DeepDyve Pubget Overpricing