Simvastatin attenuates renal ischemia/reperfusion injury from oxidative stress via targeting Nrf2/HO-1 pathway.

Abstract

Ischemia-reperfusion (I/R) injury of the kidneys is commonly encountered in the clinic. The present study assessed the efficacy of simvastatin in preventing I/R-induced renal injury in a rat model and investigated the corresponding molecular mechanisms. Rats were divided into 3 groups, including a sham, I/R and I/R + simvastatin group. The results revealed that in the I/R group, the levels of blood urea nitrogen, serum creatinine and lactate dehydrogenase were significantly higher than those in the sham group, which was significantly inhibited by simvastatin pre-treatment. I/R significantly decreased superoxide dismutase activity compared with that in the sham group, which was largely rescued by simvastatin. Furthermore, I/R significantly increased the malondialdehyde content compared with that in the sham group, which was reduced by simvastatin. Hematoxylin-eosin staining revealed no obvious morphological abnormalities in the sham group, while I/R led to notable tubular cell swelling, vacuolization, cast formation and tubular necrosis, which was rescued by simvastatin. A terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay demonstrated that I/R significantly increased the number of apoptotic cells compared with that in the sham group, which was significantly inhibited by simvastatin. Western blot analysis demonstrated that simvastatin upregulated I/R-induced increases of nuclear factor erythroid-2-related factor 2 (Nrf2) and anti-oxidant enzyme heme oxygenase-1 (HO-1). Reverse-transcription quantitative PCR indicated that changes in the mRNA levels of Nrf2 and HO-1 were consistent with the western blot results. It was concluded that simvastatin treatment led to upregulation of HO-1 protein levels through activating the Nrf2 signaling pathway to ultimately protect the kidneys from I/R-associated oxidative damage.