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

Abstract

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-3β (GSK-3β)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related proteins in rats 4 hr 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-3β inhibitor SB216367 promoted phosphorylation of GSK-3β, 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 (α2-AR) antagonist atipamezole and imidazoline I 2 receptor (I 2 R) antagonist idazoxan reversed the effects of DEX. These results suggest that the renoprotective effects of DEX are mediated via α2-AR and I 2 R-dependent pathways that reduce inflammation and oxidative stress through GSK-3β/Nrf2 signaling.

• Authors: Xiujing Feng, Wei Guan, Yuan Zhao, Chaoran Wang, Manyu Song, Yujie Yao, Tianyuan Yang, Honggang Fan
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 234 Issue 10 Pg. 18994-19009 (08 2019) ISSN: 1097-4652 [Electronic] United States
• PMID: 30919976 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Anti-Inflammatory Agents
• Lipopolysaccharides
• NF-E2-Related Factor 2
• Nfe2l2 protein, rat
• Dexmedetomidine
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat

Topics

• Acute Kidney Injury (drug therapy, pathology)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Dexmedetomidine (pharmacology)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Inflammation (drug therapy)
• Kidney Tubules (pathology)
• Lipopolysaccharides (toxicity)
• Male
• NF-E2-Related Factor 2 (metabolism)
• Oxidative Stress (drug effects)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)