Downregulation of Cx43 reduces cisplatin-induced acute renal injury by inhibiting ferroptosis

Abstract

Ferroptosis is one of the main mechanisms involved in different forms of acute kidney injury (AKI), including cisplatin-induced AKI. However, it is not clear whether Cx43 has a regulatory effect on ferroptosis caused by cisplatin. In this study, we investigate the regulatory effects of Cx43 on cisplatin-induced ferroptosis and its mechanism. In vivo and in vitro studies showed that the expression level of Cx43 was significantly upregulated in the cisplatin-induced kidney injury model. In HK2 cells, cisplatin significantly induced ferroptosis. Adding shRNA-Cx43 and gap27 to the HK2 cells downregulated the expression of Cx43 and blocked the effects of cisplatin, resulting in a significantly improved survival rate of HK2 cells. Our primary data suggested that downregulating Cx43 not only inhibits ferroptosis, but also inhibits apoptosis. Through mechanistic studies, we confirmed that downregulating the expression of Cx43 by increasing SLC7A11 can increase the GSH content to inhibit cisplatin-induced ferroptosis. In vivo experiments showed that downregulation of Cx43 expression by gap27 reduced AKI in the animal model by inhibiting cisplatin-induced ferroptosis. Therefore, our results indicated that downregulation of Cx43 can inhibit ferroptosis by restoring the level of SLC7A11 in the system x_c‾ transporter and alleviate cisplatin-induced AKI.

Keywords: Cisplatin; Connexin43; Ferroptosis; SLC7A11.