Cdk5-Mediated Phosphorylation of Sirt1 Contributes to Podocyte Mitochondrial Dysfunction in Diabetic Nephropathy

Aims:Mitochondrial dysfunction contributes to podocyte injury, which is the leading cause of proteinuria in diabetic nephropathy (DN). In this study, we explored the role of cyclin-dependent kinase 5 (Cdk5) in mitochondrial dysfunction of podocytes under diabetic conditions. Results:Our results showed that the expression and activity of Cdk5 were significantly upregulatedin vivoandin vitrounder diabetic conditions, accompanied by the downregulation of synaptopodin and nephrin, as well as structural and functional mitochondrial dysfunction. Inhibition of Cdk5 with roscovitine or dominant-negative Cdk5 led to the attenuation of podocyte injury by upregulating synaptopodin and nephrin. The inhibition of Cdk5 also ameliorated mitochondrial dysfunction by decreasing reactive oxygen species levels and cytochrome c release, while increasing adenosine triphosphate production. Sirt1, an NAD(+)-dependent deacetylase, was decreased in podocytes with high glucose (HG) treatment; however, its phosphorylation level at S47 was significantly upregulated. We demonstrated that HG levels cause overactive Cdk5 to phosphorylate Sirt1 at S47. Suppression of Cdk5 reduced Sirt1 phosphorylation levels and mutation of S47 to nonphosphorable alanine (S47A), significantly attenuated podocyte injury and mitochondrial dysfunction in diabetic conditionin vivoandin vitro. Innovation and Conclusion:Our study has demonstrated the role of Cdk5 in regulating mitochondrial function through Sirt1 phosphorylation and thus can potentially be a new therapeutic target for DN treatment. IRB number: 20190040.

Automated summary

This study demonstrated that in diabetic conditions, the overactivity of Cdk5 leads to podocyte injury and mitochondrial dysfunction, whereas inhibition of Cdk5 can attenuate these injuries and dysfunctions by modulating Sirt1 phosphorylation. This suggests that Cdk5 may be a potential therapeutic target for the treatment of DN.