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Sildenafil Prevents Podocyte Injury via PPAR-γ-Mediated TRPC6 Inhibition
Ramon Sonneveld1, Joost G Hoenderop2, Andrea M Isidori3
1Departments of Nephrology.
Insights
Sildenafil reduces kidney injury by inhibiting TRPC6 expression via a PPAR-γ pathway. This mechanism, involving peroxisome proliferator-activated receptor gamma (PPAR-γ), offers a potential treatment for proteinuric glomerular diseases.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Gain-of-function mutations and overexpression of Transient Receptor Potential Channel C6 (TRPC6) in podocytes cause glomerular injury and proteinuria.
- Sildenafil is known to reduce TRPC6 expression and activity in nonrenal cells, but the underlying mechanism remains unclear.
- Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a downstream target in the cyclic guanosine monophosphate (cGMP)-activated protein kinase G (PKG) pathway, and its agonists show antiproteinuric effects.
Purpose of the Study:
- To investigate the hypothesis that sildenafil inhibits TRPC6 expression in podocytes through PPAR-γ-dependent mechanisms.
- To determine if this inhibition counteracts podocyte injury and proteinuria.
Main Methods:
- In vitro studies using podocytes treated with sildenafil, 8-bromoguanosine 3',5'-cyclic monophosphate sodium salt (8-Br-cGMP), or pioglitazone.
- Assessment of TRPC6 expression, promoter activity, and calcium influx, with manipulation of PKG and PPAR-γ pathways using knockdown or antagonists.
- In vivo studies in rat and mouse models of nephropathy (adriamycin-induced) and hyperglycemia, evaluating proteinuria and TRPC6 expression.
Main Results:
- Sildenafil, 8-Br-cGMP, and pioglitazone dose-dependently downregulated TRPC6 expression in podocytes.
- PKG or PPAR-γ inhibition enhanced TRPC6 expression and counteracted the effects of sildenafil and 8-Br-cGMP, indicating a role for these pathways.
- PPAR-γ was shown to bind to the TRPC6 promoter, and sildenafil/pioglitazone treatment prevented proteinuria and reduced TRPC6 expression in animal models.
Conclusions:
- Sildenafil ameliorates podocyte injury and prevents proteinuria by inhibiting TRPC6 expression via cGMP/PKG-dependent PPAR-γ binding to the TRPC6 promoter.
- This mechanism suppresses TRPC6 promoter activity, expression, and activity, offering a novel therapeutic insight.
- Given sildenafil's clinical approval, further investigation into its antiproteinuric potential for glomerular diseases is warranted.
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.
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