缺血性脑卒中是我国非传染性致死致残的重要原因，造成沉重的社会负担，高血压是其首要危险因素。已证实，WNK-SPAK/OSR1-NKCC1信号通路与高血压密切相关。课题组前期研究发现，自发性高血压大鼠WNK信号表达水平高于正常鼠，其发生缺血性脑卒中后脑损伤趋于严重；抑制WNK信号通路，可减轻脑损伤程度。基于此，提出研究假设：WNK信号通路可能参与高血压合并缺血性脑卒中后脑损伤的致病过程。本项目拟进行以下研究：(1) 分析WNK-SPAK/OSR1-NKCC1通路在高血压和缺血性脑卒中时的表达及与脑损伤的相关性；(2) 探讨SPAK阻断剂对高血压合并缺血性脑卒中所致脑损伤的保护作用；(3) 在临床病例中验证WNK-SPAK/OSR1-NKCC1通路与高血压合并缺血性脑卒中所致脑损伤的相关性。本项目将为明确缺血性脑卒中的发病机制提供新证据，也将为治疗缺血性脑卒中尤其是高血压合并脑卒中提供新靶点。

Ischemic stroke is mainly responsible for non-infectious death and disability in China, leading to heavy social burdens. Hypertension is the first risk factor of ischemic stroke. Recently, it is found that the signaling pathway consisting of the with-no-lysine (K) kinases (WNK), Ste20-related proline alanine-rich kinase (SPAK) and the downstream Na-K-Cl cotransporter (NKCC1) is closely associated with pathogenesis of hypertension. Our recent studies have shown that up-regulation of WNK signaling in spontaneously hypertensive rats may contribute to the worsened ischemic stroke brain injury and that blocking WNK signaling pathway could reduce ischemic brain damage. Therefore, we speculate that WNK signaling pathway may be associated with the pathogenesis of ischemic brain damage caused by ischemic stroke accompanied with hypertension. In this proposal, we plan to use the hypertensive mice and patients with ischemic stroke to confirm three important issues as followings: (1) the expression of WNK-SPAK/OSR1-NKCC1 signaling proteins after hypertension and ischemic stroke, and the correlation of the expression level of these proteins with the degree of brain damage; (2) the protective effect of SPAK inhibitor on brain damage caused by ischemic stroke accompanied with hypertension; (3) the correlation of WNK-SPAK/OSR1-NKCC1 signaling pathway and ischemic brain damage in clinical cases. This study will provide new evidences to explain the pathogenesis of ischemic stroke, and may discover new therapeutic targets for treatment of ischemic stroke especially ischemic stroke accompanied with hypertension.