The Effect Of Dexmedetomidine On SAKI Of Rats Through The GSK-3?-mediated Activation Of Nrf2/ARE Signaling Pathway

Sepsis-induced Acute Kidney Injury?SAKI?is a veterinary clinical high fatality infection complication.Exploring the effective prevention and treatment of drugs and elucidating key pharmacodynamic mechanisms are the focus of research in this field.Previous studies on the pathophysiology of SAKI have focused on inflammatory responses,and the focus of the research in recent years has begun to change to oxidative stress injury.Dexmedetomidine?DEX?as an?₂adrenergic receptor agonist not only has effects on sedative,analgesic,anti-anxiety,hypnotic,etc.,but also reduces inflammatory and oxidative stress factors,inhibits apoptosis,etc.In our previous study found that DEX can reduce abnormally elevated reactive oxygen species?ROS?in rats'SAKI and reduce their SAKI damage.Therefore,in this study,we use the rat SAKI model as the research object with intervening of DEX and receptor antagonist.The pathological examination of the rat kidney and the detection of major injury indicators such as ROS,MDA and SOD were used to investigate the anti-oxidative stress effect of DEX on rat SAKI damage and its possible causes.And by detecting the expression levels of Nrf2,HO-1 and NQO1 proteins to confirm the relationship between DEX and Nrf2/ARE and action receptors in DEX protects rat SAKI.And by using the inhibitor SB216763 to study the effect of GSK-3?in the DEX regulates Nrf2/ARE signaling pathway.To find out the protective mechanism and correlated regulatory receptors of how DEX activates Nrf2/ARE signaling pathway in SAKI model.It will provide theoretical basis and experimental basis for future research on SAKI treatment and related mechanism study as well as the experimental evidence for clinical application of DEX.48 cases of healthy SD rats were selected and randomly divided into eight groups:control group,SAKI model group?LPS 10 mg/kg,ip?,Dexmedetomidine group?DEX 30?g/kg+LPS 10mg/kg?.Kg,ip),GSK-3?inhibitor group?SB216763 10 mg/kg+LPS 10 mg/kg,ip?,Atipamezole group?Atip 250?g/kg+DEX 30?g/kg+LPS 10 mg/kg,ip?,Idazoxan group?IDA 1.5 mg/kg+DEX 30?g/kg+LPS 10 mg/kg,ip?,Double rivalry agent group?Atip 250?g/kg+IDA 1.5 mg/kg+DEX 30?g/kg+LPS 10 mg/kg Ip?,solvent group?SB216763 solvent+LPS 10 mg/kg,ip?.Rats were sacrificed after 4 h of LPS injection and kidneys were taken for use.The experimental results show that:from the pathological changes in the kidney,after the establishment of the SKAI model,the rat kidney showed significant damage,the pathological changes were more severe than the control group.After administration of DEX,the damage of SAKI was significantly improved,and the GSK-3?inhibitor group also significantly improved the damage of SAKI.The detection of various indicators showed that the ROS and MDA content in the SAKI model group increased significantly?P?0.05?,and SOD,GSH,CAT activities in the group were significantly reduced?P?0.05?.After intervention with DEX,the ROS concentration and MDA content in kidneys all decreased significantly?P?0.05?,and the activity of SOD,GSH,and CAT increased significantly?P?0.05?,the body's ability to resist oxidative stress was obviously improved.The expression of Nrf2,HO-1 and NQO1 protein in the model group was significantly higher than that in CON group?P?0.05?.The expression of Nrf2,HO-1 and NQO1 protein in DEX group was significantly higher than that in model group.The expression of Nrf2,HO-1 and NQO1protein in the DEX group was significantly increased?P?0.05?than the modal group.However,the protective effect of the DEX group was effectively reversed in both the Atipamezole group and the Double rivalry agent group.After administration of SB216763,the ROS concentration and MDA content in the GSK-3?inhibitor group were significantly lower than those in the SAKI model group?P?0.05?,and the SOD,GSH,CAT,and Nrf2 related proteins were significantly increased.?P?0.05?.The GSK-3?inhibitor group had similar results to the DEX trend.Summarize the results of the above test,it can conclude that:?1?DEX can protect rat SAKI by antioxidant stress.?2?DEX can protect rat SAKI by increasing the phosphorylation of GSK-3?and regulating Nrf2/ARE signal transduction pathway.?3?DEX can regulate GSK-3?/Nrf2/ARE by the?₂ receptor and I₂ receptor,and among which the?2 receptor is more important.