TEAD1 Prevents Necroptosis and Inflammation in Cisplatin-Induced Acute Kidney Injury Through Maintaining Mitochondrial Function.

Abstract

Cisplatin is widely used for the treatment of solid tumors and its antitumor effects are well established. However, a known complication of cisplatin administration is acute kidney injury (AKI). In this study, we examined the role of TEA domain family member 1 (TEAD1) in the pathogenesis of cisplatin-induced AKI. TEAD1 expression was upregulated in tubular epithelial cells of kidneys with cisplatin-induced AKI. TEAD1 floxed mice (TEAD1^CON) mice treated with cisplatin developed tubular cell damage and impaired kidney function. In contrast, proximal tubule specific TEAD1 knockout (TEAD1^PKO) mice treated with cisplatin had enhanced tubular cell damage and kidney dysfunction. Additionally, TEAD1^PKO mice treated with cisplatin had augmented necroptotic cell death and inflammatory response compared to TEAD1^CON mice with cisplatin. Knockdown of TEAD1 in mouse tubular epithelial cells showed increased intracellular ROS levels, reduced ATP production and impaired mitochondrial bioenergetics compared to control cells treated with cisplatin. Mechanistically, TEAD1 interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, to promote mitochondrial function. Taken together, our results indicate TEAD1 plays an important role in the pathogenesis of cisplatin-induced AKI through regulation of necroptosis and inflammation, which is associated with mitochondrial metabolism. Therefore, TEAD1 may represent a novel therapeutic target for cisplatin-induced AKI.