Postconditioning protects renal fibrosis by attenuating oxidative stress-induced mitochondrial injury.

Abstract

Epithelial-mesenchymal transition (EMT) plays a critical role in renal fibrosis. We hypothesize that mitochondrial DNA damage and DNA deletions caused by reactive oxygen species (ROS) during renal ischemia-reperfusion injury (IRI) might lead to EMT in renal fibrosis. Rats were classified into seven groups: sham-operation, IRI, postconditioning (POC), I/R + apocynin, POC + apocynin, I/R + Mito-Tempol (Mito-T) and POC + Mito-T. These groups were monitored for up to 3 months. Serum creatinine, renal histopathology changes and mitochondrial oxidative stress were examined. We also treated NRK52E cells with 200 μM hydrogen peroxide to evaluate the effect of ROS on EMT development, and with 400 ng/mL ethidium bromide to assess the extent of mitochondrial DNA depletion during EMT. Three months after IRI injury, the IRI group showed significant renal fibrosis, increased generation of ROS and higher mitochondrial DNA damage and DNA deletions. However, the severity of renal fibrosis and mitochondrial oxidative stress were markedly attenuated in the POC group. Studies on NRK52E cells showed that mitochondrial DNA damage triggered the development of EMT. Mitochondrial DNA damage induced by elevated ROS production likely leads to EMT, and might further result in renal fibrosis. POC treatment might attenuate the degree of renal fibrosis by protecting mitochondria from oxidative stress-induced mitochondrial DNA damage.