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Sildenafil Prevents Podocyte Injury via PPAR-γ–Mediated TRPC6 Inhibition

Ramon Sonneveld, Joost G. Hoenderop, Andrea M. Isidori, Carole Henique, Henry B. Dijkman, Jo H. Berden, Pierre-Louis Tharaux, Johan van der Vlag and Tom Nijenhuis
JASN May 2017, 28 (5) 1491-1505; DOI: https://doi.org/10.1681/ASN.2015080885
Ramon Sonneveld
Departments of *Nephrology,
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Joost G. Hoenderop
†Physiology, and
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Andrea M. Isidori
‡Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy;
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Carole Henique
§Paris Cardiovascular Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France;
‖Sorbonne Paris Cité, Université Paris Descartes, Paris, France; and
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Henry B. Dijkman
¶Pathology, Radboud University Medical Center, Nijmegen, The Netherlands;
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Jo H. Berden
Departments of *Nephrology,
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Pierre-Louis Tharaux
§Paris Cardiovascular Centre, Institut National de la Santé et de la Recherche Médicale, Paris, France;
‖Sorbonne Paris Cité, Université Paris Descartes, Paris, France; and
**Service de Néphrologie, Hôpital Européen Georges Pompidou, Paris, France
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Johan van der Vlag
Departments of *Nephrology,
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Tom Nijenhuis
Departments of *Nephrology,
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Abstract

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.

  • albuminuria
  • ion channel
  • podocyte
  • signaling
  • glomerulosclerosis
  • focal segmental glomerulosclerosis
  • Copyright © 2017 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 28 (5)
Journal of the American Society of Nephrology
Vol. 28, Issue 5
May 2017
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Sildenafil Prevents Podocyte Injury via PPAR-γ–Mediated TRPC6 Inhibition
Ramon Sonneveld, Joost G. Hoenderop, Andrea M. Isidori, Carole Henique, Henry B. Dijkman, Jo H. Berden, Pierre-Louis Tharaux, Johan van der Vlag, Tom Nijenhuis
JASN May 2017, 28 (5) 1491-1505; DOI: 10.1681/ASN.2015080885

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Sildenafil Prevents Podocyte Injury via PPAR-γ–Mediated TRPC6 Inhibition
Ramon Sonneveld, Joost G. Hoenderop, Andrea M. Isidori, Carole Henique, Henry B. Dijkman, Jo H. Berden, Pierre-Louis Tharaux, Johan van der Vlag, Tom Nijenhuis
JASN May 2017, 28 (5) 1491-1505; DOI: 10.1681/ASN.2015080885
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Keywords

  • albuminuria
  • ion channel
  • podocyte
  • signaling
  • glomerulosclerosis
  • focal segmental glomerulosclerosis

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