Enhanced renoprotective effects of remote ischemic postconditioning and alpha-lipoic acid via modulation of TLR4/MyD88/NF-κB and Nrf2/HO-1 pathways in renal ischemia-reperfusion injury.

This study aimed to evaluate the renoprotective benefits of remote ischemic postconditioning (RIPostC) and alpha-lipoic acid)ALA( against acute kidney injury (AKI) secondary to ischemia-reperfusion, focusing on the role of the TLR4/MyD88/NF-κB signaling cascade and the involvement of Nrf2 and HO-1. Individual and combined therapy approaches were tested. Thirty-five male Sprague-Dawley rats were randomly assigned to five groups, with seven rats in each group: sham, I/R, I/R + RIPostC, ALA + I/R, ALA + I/R + RIPostC. The kidney ischemia-reperfusion injury (IRI) model was established by occluding the renal pedicles for 60 min, followed by 24 h reperfusion. As soon as blood flow was restored to the kidney, RIPostC was applied by blocking and then unblocking the main artery in the left leg for five minutes each, repeating this process three times in a row. After 24 h of reperfusion, blood and urine samples and kidney tissues were harvested for renal function, histopathological, oxidative stress, and inflammatory marker assessments. I/R caused notable renal impairment, increased fractional excretion of sodium, decreased urine osmolality and creatinine clearance, heightened oxidative stress, and histopathological injury in rats. Accordingly, the pro-inflammatory mediators TLR4, MyD88, and NF-κB were upregulated, whereas the cytoprotective markers Nrf2 and HO-1 were downregulated. Both RIPostC and ALA treatment attenuated the I/R-induced renal injury, as demonstrated by improved histopathological outcomes, reduced total oxidant status (TOS), increased total antioxidant capacity (TAC), reduced inflammation, and improved renal function. Furthermore, combination therapy (ALA+I/R+RIPostC) had greater antioxidant effects, as evidenced by increased Nrf2 and HO-1 expression levels compared to all other groups. The current data reveal that RIPostC and ALA protect against renal IRI by down-regulating the TLR4/MyD88/NF-κB signaling pathway and enhancing Nrf2/HO-1 expression-mediated anti-inflammatory and antioxidative effects.