Recent studies have demonstrated upregulation of transient receptor potential cation channel 6 (TRPC6) contributes to podocyte injury in acquired forms of proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS). However, under these pathophysiological conditions, the mechanisms of regulation of TRPC6 expression and activity remain unknown. The present study tested the hypothesis that NADPH oxidase-mediated redox signaling importantly participates in the development of podocyte injury by regulation of TRPC6 expression and activity. Injection of puromycin aminonucleoside (PAN) to rats produced severe proteinuria and mimics the lesions of FSGS. Podocyte effacement, NADPH oxidase subunit NOX4 expression, enzyme activity and TRPC6 expression were significant increased in glomeruli from PAN nephrosis rats. Inhibition of NADPH oxidase activity by apocynin ameliorated proteinuria and podocyte effacement and reduced TRPC6 expression. In in vitro study, PAN significantly increased NOX4 and TRPC6 expression levels in cultured podocytes. This increased TRPC6 expression was attenuated by apocynin or siRNA-NOX4. Our results provide direct evidence for the first time that NADPH oxidase-derived reactive oxygen species (ROS) is one of critical components of a signal transduction pathway that links PAN nephrosis to TRPC6-mediated Ca2+ signaling.

Keywords:
Oxidative stress, Podocyte injury, TRPC6, Focal segmental glomerulosclerosis
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© 2009 S. Karger AG, Basel
2009
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