Regulation of oxidative stress and inflammation in ischemia/reperfusion-induced acute kidney injury

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Wang, Pengqi
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Renal ischemia/reperfusion (I/R) is a main cause of acute kidney injury (AKI) and delayed graft function after renal transplantation. Previous studies in human and experimental models have identified that inflammation and oxidative stress are two key players in renal I/R injury. However, the underlying mechanisms remain speculative. The overall objective of the study was to investigate the biochemical and molecular mechanisms of I/R-induced renal injury and the effect of tyrosol supplementation on I/R-induced kidney oxidative stress damage. In the present study, renal I/R was induced in Sprague-Dawley rats and in a human kidney proximal tubular cell line. A significantly elevated expression of pro-inflammatory cytokine expression (MCP-1, IL-6) was observed. There was a significant decrease in mRNA and protein levels of two hydrogen sulphide (H2S)-producing enzymes, CBS and CSE, with a concomitant reduction of glutathione and H2S production. In the cell culture model, hypoxia–reoxygenation of proximal tubular cells led to a decrease in CBS and CSE expression and an increase in pro-inflammatory cytokine expression. Supplementation of glutathione or H2S donor (NaHS) effectively abolished cytokine expression in tubular cells. Experiments were conducted to detect oxidative stress markers. It was demonstrated that there was a significant increase in peroxynitrite formation and lipid peroxidation in the kidney after I/R insult, which might be caused by the elevation in nitric oxide (NO) metabolites and inducible nitric oxide synthase (iNOS). Administration of tyrosol, a natural phenolic compound, reduced peroxynitrite formation, lipid peroxidation and the level of NO metabolites via inhibiting NF-B activation and iNOS expression. Tyrosol treatment improved kidney function and had a protective effect against I/R-induced AKI. The present study has clearly demonstrated that (1) there is a reduction of H2S production via inhibition of CBS and CSE expression, which contributes to increased pro-inflammatory cytokine expression in the kidney and in tubular cells upon I/R insult; (2) restoration of endogenous H2S production would be of therapeutic value in regulating inflammatory response in I/R-induced kidney injury; (3) tyrosol treatment has a beneficial effect against renal I/R-induced oxidative stress, in part, through its inhibition on NF-B activation and iNOS-mediated NO production.
Acute kidney injury, Ischemia/reperfusion, Oxidative stress, Inflammation