右美托咪定对犬脓毒血症致急性肾损伤保护机制及药效靶位的确证

脓毒血症致急性肾损伤（SAKI）是兽医临床高致死率的感染并发症。探寻有效防治药物及阐明关键药效机制的是该领域的研究焦点，以往对SAKI的病理生理学机制研究多集中在炎症反应方面，近年来研究的关注点开始向氧化应激损伤方面转移。课题组前期研究发现DEX对犬SAKI具有保护作用和减轻氧化应激损伤现象。因此课题组建立SAKI模型，应用DEX进行干预。从抑制氧化应激因子生成角度，探讨DEX通过胆碱能通路对NF-κB—iNOS—NO的调控机制；从加速清除氧化应激因子角度，探讨DEX激活PI3K/Akt后，以GSK-3β为关键位点调控Nrf2/ARE的作用机制。以此为基础，通过调控α2-AR及I2R，探寻DEX药效靶位，进一步完善其药理作用分子机制，为今后临床开展SAKI的治疗及进行相关的机制研究提供理论依据及试验基础。

Acute renal injury caused by sepsis (SAKI) is a veterinary clinical high mortality rate (death rate) of infection complications. It is the focus of researches in this field to explore the effective prevention and treatment of drugs and to clarify the key mechanism of efficacy. In Previous studies, the inflammatory response is the focus of researches in SAKI on the pathophysiological mechanisms, in recent years, the relevant studies has shifted to oxidative stress injury. Our preliminary studies have found that DEX has a significant protective effect and can reduce oxidative stress injury in canine with SAKI. Therefore, our research group will establish the model of DEX intervening acute renal injury caused by sepsis. From the perspective of inhibiting oxidative stress factor generated, the purpose of this study is exploring the regulation mechanism of cholinergic anti-inflammatory pathway on NF-κB—iNOS—NO by the activation of DEX; Simultaneously, from the perspective of clearing the oxidative stress factor, we will research whether GSK-3β can be as a key site to regulate Nrf2/ARE through DEX activating PI3K/Akt. Based on the mentioned research foundation, we plan to explore the DEX efficacy target through the regulation of α2-AR and I2R, to further perfecting its molecular mechanism of pharmacological mechanism. This will pave a new way to provide the theoretical basis for the future clinical application of DEX in the treatment of canine SAKI and lay a foundation for revealing the protective mechanism.