Nobiletin alleviates ischemia/reperfusion injury in the kidney by activating PI3K/AKT pathway

Recent studies have demonstrated that nobiletin (NOB) displays anti-oxidative and anti-apoptotic efficacies against multiple pathological insults. However, the potential effects of NOB on the injury caused by ischemia and reperfusion (I/R) in the kidney remain undetermined. In the present study, I/R injury was elicited by right kidney removal and left renal pedicel clamping for 45 min, followed by reperfusion for 24 h. NOB was added at the start of reperfusion. Histological examination, detection of biomarkers in plasma, and measurement of apoptosis induced by endoplasmic reticulum stress (ERS) were used to evaluate renal injury. Additionally, the PI3K/AKT inhibitor LY294002 was also used in mechanistic experiments. NOB pre-treatment significantly reduced renal damage caused by I/R injury, as indicated by decreased serum levels of creatine, blood urea nitrogen and tubular injury scores. Furthermore, NOB inhibited elevated ERS-associated apoptosis, as evidenced by reduced apoptotic rates and ERS-related signaling molecules (such as, C/EBP homologous protein, caspase-12 and glucose-regulated protein of 78 kDa). NOB increased phosphorylation of proteins in the PI3K/AKT pathway. The inhibition of PI3K/AKT signaling with pharmacological inhibitors could reverse the beneficial effects of NOB during renal I/R insult. In conclusion, NOB pre-treatment may alleviate I/R injury in the kidney by inhibiting reactive oxygen species production and ERS-induced apoptosis, partly through the PI3K/AKT signaling pathway.