Dexmedetomidine ameliorates lipopolysaccharide-induced acute kidney injury in rats by inhibiting inflammation and oxidative stress via the GSK-3β/Nrf2 signaling pathway

Acute kidney injury (AKI) is a frequent and serious complication of sepsis; however, there are currently no effective therapies. Inflammation and oxidative stress are the major mechanisms implicated in lipopolysaccharide (LPS)-induced AKI. Dexmedetomidine (DEX) has been reported to have remarkable anti-inflammatory and antioxidant effects. Here, we examined the renoprotective effects of DEX and potential underlying mechanisms in rats with LPS-induced AKI. We analyzed renal function and structure; serum inflammatory cytokine; renal oxidant and antioxidant levels; and renal expression of glycogen synthase kinase-3 beta (GSK-3 beta)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related proteins in rats 4hr after administration of LPS. Pretreatment with DEX improved renal function and significantly reduced the levels of inflammatory cytokines and oxidative stress markers. Treatment with DEX and the GSK-3 beta inhibitor SB216367 promoted phosphorylation of GSK-3 beta, induced Nrf2 nuclear translocation, and increased transcription of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone oxidoreductase-1, primarily in renal tubules. Alpha-2-adrenergic receptor (alpha 2-AR) antagonist atipamezole and imidazoline I (2) receptor (I R-2) antagonist idazoxan reversed the effects of DEX. These results suggest that the renoprotective effects of DEX are mediated via alpha 2-AR and I R-2-dependent pathways that reduce inflammation and oxidative stress through GSK-3 beta/Nrf2 signaling.