Ranolazine Protects the Kidney from Ischemia/Reperfusion Injury in Adult Male Rats by Modulation of Inflammatory and Oxidative Pathways and Suppression of Notch2/Hes1 signaling pathway

Background: Renal ischemia and reperfusion is the main cause of acute injury of the kidney and associated with increase morbidity, mortality, and long stage hospitalization. Renal ischemia and reperfusion occur in approximately 10-20% of kidney transplant recipients. If ischemia and reperfusion occur, this will induce oxidative stress, inflammatory process and apoptosis. Objectives: This research aimed to investigate the possible nephroprotective effect of ranolazine in renal ischemia reperfusion injury in rat model by targeting Notch2/Hes1 signaling pathway. Materials & Methods: 24 adult male Wistar Albino rats were divided randomly into 4 groups (six rats in each group): Sham group underwent laparotomy without induction of ischemia reperfusion, Control group (Rats underwent 30 minutes bilateral renal ischemia followed by 2 hours reperfusion, Vehicle group (same as in control group + DMSO), Ranolazine group (same as in control group + 30mg/kg ranolazine). After 2 hrs of reperfusion, the kidney and blood were harvested. Blood sample was used to assess serum creatinine and blood urea nitrogen (S.cr &BUN). Renal tissue was used to assess IL-1B, HMG box1, F2-isoprostane and Notch2/Hes1 as well as histological examination. Results: At the end of experiment, S.cr, BUN and renal tissue level of HMG box1, IL-1s, F2-isoprostane, and Notch2/Hes1 were significantly increased in control group as compared with sham group. Histopathology study demonstrated severe kidney injury in the control group as compared with sham group. Kidneys of rats in ranolazine treated group demonstrated functional and histological improvement by significant decrease S.cr., BUN, renal tissue level of HMG box1, IL-1s, F2-isoprostane, Notch2/Hes1, and severity score of tubular injury also significantly decreased in ranolazine treated group as compared with control and vehicle groups. Conclusion: From the overall results, ranolazine significantly decreases renal ischemia reperfusion injury in rats which was achieved by modulation of inflammatory response through significant reduction in renal tissue level of HMG box1, IL-1s, and down regulation of Notch2/Hes1 signaling pathway, and anti-oxidant effect via significant reduction in F2- isoprostane level.