Remote ischemic preconditioning for kidney protection: GSK3β-centric insights into the mechanism of action.
Remote ischemic preconditioning for kidney protection: GSK3β-centric insights into the mechanism of action.
复制标题
肾脏保护的远程缺血预处理：以GSK3β为中心的作用机理的见解。
DOI：
10.1053/j.ajkd.2015.06.026
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发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Gong R
中科院分区：
文献类型：
--
作者：
Liu Z;Gong R
预防药物干预后高危患者的急性肾损伤(AKI)是临床实践面临的最大挑战。动物实验和临床试验的最新数据表明，以肢体IPC为代表的远程缺血预适应(IPC)对肾脏具有保护作用。IPC可有效降低心血管干预和使用碘化放射造影剂后发生急性心肌梗死的风险。然而，这种保护作用的潜在机制仍然难以捉摸。保护性信号通过多条潜在的通讯途径从接受IPC的偏远部位(如肢体)传递到靶器官(如肾脏)，这可能涉及体液、神经和全身机制。不同的信号传导通路触发了多种信号转导通路，包括再灌注损伤抢救激酶和Survior激活因子增强通路，所有这些通路都汇聚在糖原合成酶β上。抑制缺血预适应后的Gsk3β可增强NRF2介导的抗氧化防御，降低依赖于NFκB的促炎反应，并发挥脱敏线粒体通透性转变所产生的生存效应。因此，IPC以GSK3β为靶点，或用FDA批准的具有GSK3β抑制活性的现有药物进行药物预适应治疗，可能是一种实用且经济有效的肾脏保护和预防AKI的辅助策略。
Preventing acute kidney injury (AKI) in high-risk patients following medical interventions is a paramount challenge for clinical practice. Recent data from animal experiments and clinical trials indicate that remote ischemic preconditioning (IPC), represented by limb IPC, confers a protective action on the kidney. IPC is effective in reducing the risk of AKI following cardiovascular interventions and the use of iodinated radiocontrast media. Nevertheless, the underlying mechanisms for this protective effect remain elusive. A protective signal is conveyed from the remote site undergoing IPC, like the limb, to target organs, like the kidney, via multiple potential communication pathways, which may involve a humoral, neuronal, and systemic mechanisms. Diverse transmitting pathways trigger a variety of signaling cascades, including the reperfusion injury salvage kinase and survivor activating factor enhancement pathways, all of which converge on glycogen synthase kinase (GSK)3β. Inhibition of GSK3β subsequent to IPC reinforces the Nrf2-mediated antioxidant defense, diminishes the NFκB-dependent pro-inflammatory response, and exerts prosurvival effects ensuing from the desensitized mitochondria permeability transition. Thus, therapeutic targeting of GSK3β by IPC or by pharmacologic preconditioning with existing FDA-approved drugs having GSK3β inhibitory activities might represent a pragmatic and cost-effective adjuvant strategy for kidney protection and prophylaxis against AKI.