CDCT‐induced nephrotoxicity in rat by apoptosis via metabolic disturbance

Abstract

AbstractCompound diclofenac sodium chlorphenamine maleate tablets (CDCT) are widely used for the cold in Asia. However, CDCT can cause hematuria symptoms in clinical, and the underlying mechanism is unknown. This study aims to investigate the CDCT‐induced changes of morphology in kidney and metabolites and further explore the possible mechanisms of CDCT‐induced nephrotoxicity. Sprague–Dawley rats were exposed to the CDCT at a clinical equivalent dose for 6 days. CDCT exposure can induce kidney injury and death. Pathological changes, including creatinine, urea nitrogen, and histopathology, were observed in rats. Furthermore, metabolomic‐driven energy and glycerophospholipid metabolism pathway disorders, accompanied by remarkably changed key metabolites, such as succinate, leukotriene B4 (LTB4), and cardiolipin (CL), are observed in the CDCT‐induced nephrotoxicity. Functionally, succinate accumulation leads to mitochondrial damage, as evidence by the imbalance of complex I and complex II and an increase in mitochondrial reactive oxygen species (mito SOX). Meanwhile, LTB4 activated the NF‐κB signaling, as shown by increased protein of p65, phosphor‐p65, and decreased protein of IκBα and phosphor‐IκBα. Eventually, the apoptosis pathway was triggered in response to reduced CL, inflammation, and mito SOX, as demonstrated by the expression of cyt c, Bax, Bcl‐2, caspase‐3, and caspase‐9. This study indicated that CDCT‐induced metabolic disorders triggered nephrotoxicity and provided a comprehensive information to elucidate the mechanism of CDCT induced nephrotoxicity.