Resveratrol prevents Drp1‐mediated mitochondrial fission in the diabetic kidney through the PDE4D/PKA pathway

Abstract To explore the role of PDE4D in diabetic nephropathy (DN) and investigate whether resveratrol protects against DN via inhibiting PDE4D. Diabetic db/db mouse and glomerular mesangial cell line (GMCs) were used to investigate the role of PDE4D and the protective effect of resveratrol on renal fibrosis under high glucose (HG) environment. Resveratrol alleviated the progress of DN via inhibiting mitochondrial fragmentation and restoring the expression of PDE4D, PKA, phosphorylated Drp1‐Ser637 and Drp1 in kidney of db/db mice. In HG‐exposed GMCs, resveratrol treatment decreased the expression of PDE4D, increased PKA level, and inhibited Drp1‐mediated mitochondrial fission. In contrast, PDE4D over‐expression blunted the inhibitory effects of resveratrol on Drp1 expression and mitochondrial fission. Moreover, PKA inhibitor H89 blunted the effects of resveratrol on phosphorylated Drp1‐Ser637 expression and mitochondrial fission in HG‐treated GMCs. Inhibition of mitochondrial fission with Drp1 inhibitor Mdivi‐1 alleviated mitochondrial dysfunction in GMCs under HG. These findings indicate PDE4D plays an important role in the process of DN. Resveratrol attenuates the development of DN by preventing mitochondrial fission through inhibiting PDE4D, which regulates the expression of phosphorylated Drp1‐Ser637 directly.