TRPA1 promotes cisplatin-induced acute kidney injury by regulating the endoplasmic reticulum stress-mitochondrial damage

Abstract

AbstractBackground Cisplatin (DDP) is a widely used and effective chemotherapeutic agent against cancer. However, nephrotoxicity is one of the most common side effects of DDP, and it can proceed to acute kidney injury (AKI). The aim of this study was to investigate the mechanism of TRPA1 in promoting DDP-induced AKI through modulation of the endoplasmic reticulum stress (ERS)-mitochondrial damage. Methods A DDP-induced HK-2 cell model in vitro and mouse model in vivo were established and treated with the TRPA1 antagonist (HC-030031). We also used TRPA1 agonists, and treated with ERS inhibitors or GRP75 inhibitors. Renal function, histopathological changes, apoptosis, ERS and mitochondria-related proteins expression, mitochondrial changes, calcium ion concentration, cell proliferative activity, mitochondrial membrane potential (MMP), ATP, and ROS levels were also evaluated. Result DDP increased Scr and BUN levels, caused renal tissue injury and cell apoptosis, decreased ERS-related proteins GRP78, CHOP, and GRP75. The mitochondrial fusion-related proteins OPA1, MFN1, and MFN2, and mitochondrial division-related proteins p-DRP1 and MFF were elevated, DDP lead to mitochondrial dysfunction, and increased calcium ion concentration. In addition, DDP inhibited cell proliferation activity, decreased MMP and ATP levels, and increased ROS levels. In contrast, HC-030031 had protective effects against DDP-induced ERS and mitochondrial dysfunctionin vivoandin vitro. Futhermore, TRPA1 agonists promoted mitochondrial dysfunction via mitochondria-associated endoplasmic reticulum membrane. ERS inhibitors and GRP75 inhibitors increased cell proliferation activity, reduced cell apoptosis, and modulated ERS-mitochondrial damage and calcium overload to improve cell injury. Conclusion TRPA1 promotes DDP-induced AKI by regulating the ERS-mitochondrial damage.