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

Abstract

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.

Melatonin attenuates acute kidney ischemia/reperfusion injury in diabetic rats by activation of the SIRT1/Nrf2/HO-1 signaling pathway

“…Furthermore, the expression of SIRT1 was decreased in DI/R group compared with NI/R group ( P <0.05; Figure 3A,C). The Nrf2/HO-1 pathway plays an important role in antioxidant reaction [45,46]. We detected the expression of Nrf2 and HO-1 in all groups.…”

Effects of Prolonged Dietary Curcumin Exposure on Skeletal Muscle Biochemical and Functional Responses of Aged Male Rats

“…Binding buffer was added to the filter tube and centrifugation was repeated. The resulting nuclear fraction was measured for protein concentration via the Bradford method and prepared for western blotting as described above using a primary antibody (1:1000) directed against Nrf2 (Santa Cruz Biotechnology; RRID:AB_1125852) [ 93 ]. Nuclear Nrf2 expression was normalized to histone-1 protein (H1) as a control (Santa Cruz Biotechnology; RRID:AB_675641) [ 94 , 95 , 96 , 97 , 98 ].…”

Protective Role of Nrf2 in Renal Disease

“…Exendin-4 decreased renal injury in I/R and upregulated antioxidant mediators such as NQO-1, Nrf2, and SOD [ 133 ]. Simvastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, also protected from I/R kidney damage, activated Nrf2, and increased HO-1 levels [ 134 ].…”