SMYD2 Promotes Renal Tubular Cell Apoptosis and Chronic Kidney Disease Following Cisplatin Nephrotoxicity

The protein lysine methyltransferase 2 (SMYD2) can affect cell proliferation, differentiation, and survival through methylation of its histone and non-histone substrates. SMYD2 has been shown to act as an oncogene to promote disease progression in a variety of cancer diseases, but its role in chronic kidney diseases (CKD) pathogenesis has not been fully elucidated. This study aims to investigate the effect of SMYD2 on cisplatin-induced CKD and its underlying mechanisms. In this study, we found that cisplatin caused severe renal injury in mice, which was accompanied by the up-regulation of SMYD2 expression. AZ505 treatment significantly down-regulated cisplatin-induced renal injury and fibrosis. It also alleviated renal apoptosis and inhibited the phosphorylation level of NF-κB p65. Conditional knockdown of Smyd2 achieved similar effects as AZ505. In renal tubular epithelial cells, inhibition or silencing of SMYD2 down-regulated cisplatin-induced apoptotic response, while overexpression of SMYD2 induced apoptotic response and activated NF-κB in response to the up-regulation of SMYD2 expression. Up-regulation of SMYD2 induced interaction and phosphorylation of SMYD2 and NF-κB p65, and inhibition of NF-κB activation further suppressed cisplatin-induced NF-κB activation and apoptosis. The present study suggests that up-regulation of SMYD2 expression in cisplatin-induced CKD may promote apoptosis of renal tubular epithelial cells and accelerate the process of renal injury through NF-κB activation. SMYD2 may serve as a potential target for effective CKD treatment.