Abstract
Mitochondrial abnormalities contribute to the development of diabetic nephropathy (DN). However, the precise mechanisms of mitochondrial dysfunction in DN remain unclear. Transient receptor potential canonical channel-6 (TRPC6), a non-selective cation channel permeable to Ca2+, has been shown to regulate mitochondrial dynamics. This study was therefore aimed to explore the regulatory role and mechanisms of TRPC6 in high glucose (HG)-induced mitochondrial dysfunction in podocytes. Here we found that TRPC6 expression and TRPC6-induced Ca2+ influx were increased in HG-treated podocytes. Furthermore, the TRPC6 inhibitor and TRPC6 siRNA ameliorated mitochondrial dysfunction and apoptosis in HG-treated podocytes. BAPTA-AM, an intracellular calcium chelating agent, attenuated mitochondrial fission under HG conditions as well. Then, we found the activity of calpain and cyclin-dependent kinase 5 (CDK5) was markedly enhanced in HG-treated podocytes, which can be blocked by pretreatment with the TRPC6 inhibitor. Calpain-1 inhibition by calpeptin or by calpain-1 siRNA transfection not only attenuated HG-induced mitochondrial fission but also reduced the activity of CDK5. Additionally, the CDK5 inhibitor and its siRNA decreased mitochondrial fragmentation in HG-treated podocytes. Collectively, we revealed the essential role of TRPC6 in regulating HG-induced mitochondrial fission and apoptosis through the calpain-1/CDK5 pathway in human podocytes, which may provide new insights into the pathogenesis of DN.