Inhibition of TRPC 6 by protein kinase C isoforms in cultured human podocytes

Transient receptor potential canonical‐6 ( TRPC 6) ion channels, expressed at high levels in podocytes of the filtration barrier, are recently implicated in the pathogenesis of various forms of proteinuric kidney diseases. Indeed, inherited or acquired up‐regulation of TRPC 6 activities are suggested to play a role in podocytopathies. Yet, we possess limited information about the regulation of TRPC 6 in human podocytes. Therefore, in this study, we aimed at defining how the protein kinase C ( PKC ) system, one of the key intracellular signalling pathways, regulates TRPC 6 function and expression. On human differentiated podocytes, we identified the molecular expressions of both TRPC 6 and several PKC isoforms. We also showed that TRPC 6 channels are functional since the TRPC 6 activator 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG) induced Ca 2+ ‐influx to the cells. By assessing the regulatory roles of the PKC s, we found that inhibitors of the endogenous activities of classical and novel PKC isoforms markedly augmented TRPC 6 activities. In contrast, activation of the PKC system by phorbol 12‐myristate 13‐acetate ( PMA ) exerted inhibitory actions on TRPC 6 and suppressed its expression. Importantly, PMA treatment markedly down‐regulated the expression levels of PKC α, PKC β, and PKC η reflecting their activation. Taken together, these results indicate that the PKC system exhibits a ‘tonic’ inhibition on TRPC 6 activity in human podocytes suggesting that pathological conditions altering the expression and/or activation patterns of podocyte‐expressed PKC s may influence TRPC 6 activity and hence podocyte functions. Therefore, it is proposed that targeted manipulation of certain PKC isoforms might be beneficial in certain proteinuric kidney diseases with altered TRPC 6 functions.