Activated WNK3 induced by intracerebral hemorrhage deteriorates brain injury maybe via WNK3/SPAK/NKCC1 pathway
Activated WNK3 induced by intracerebral hemorrhage deteriorates brain injury maybe via WNK3/SPAK/NKCC1 pathway
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脑出血诱导的WNK3激活可能通过WNK3/SPAK/NKCC1通路加重脑损伤
DOI：
10.1016/j.expneurol.2020.113386
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发表时间：
2020-06
影响因子：
5.3
通讯作者：
Chen Gang
中科院分区：
文献类型：
--
作者：
Wu Degang;Lai Niansheng;Deng Ruming;Liang Tianyu;Pan Pengjie;Yuan Guiqiang;Li Xiang;Li Haiying;Shen Haitao;Wang Zhong;Chen Gang
研究背景脑出血（Intracerebral hemorrhage，ICH）是中老年人常见的脑部疾病，致残率和/或死亡率高，是一个严重的公共卫生问题。WNK 3激酶和WNK 3/SPAK/NKCC 1信号通路在维持正常细胞稳态中起着不可或缺的作用。然而，它们在ICH诱导的继发性脑损伤（SBI）中的作用和潜在机制尚未阐明。MethodsWe建立了一个ICH模型，使用雄性Sprague-Dawley（SD）大鼠通过注射自体动脉血到单侧基底神经节。为了建立体外ICH模型，将氧合血红蛋白（OxyHb; 20 μM）和神经元在37 °C，5%CO2气氛中培养6 h。为探讨WNK 3及其信号通路在脑出血发病中的作用，采用基因干预、旋转和水迷宫实验，检测脑水肿和神经炎症反应，并进行末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）、Fluoro-Jade C（FJC）和Nissl染色。此外，WNK 3的沉默减少了经历ICH的大鼠中的神经元凋亡和炎症反应。抑制WNK 3的表达可减轻脑出血对血脑屏障（BBB）的损害，减轻脑水肿的损害程度，改善脑出血引起的神经行为认知障碍。此外，WNK 3的过表达具有相反的效果。WNK 3/SPAK/NKCC 1信号通路可能参与了上述过程。结论WNK 3和WNK 3/SPAK/NKCC 1信号通路在ICH诱导的SBI中起着重要的生物学作用。WNK 3的缺失可减轻脑出血后的脑损伤。因此，WNK 3和WNK 3/SPAK/NKCC 1信号通路是治疗脑出血后SBI的潜在靶点。
BackgroundIntracerebral hemorrhage (ICH) is the common brain diseases in middle-aged and elderly people, with high disability and/or mortality rate, and is a serious public health concern. Both WNK3 kinase and the WNK3/SPAK/NKCC1 signaling pathway play an integral role in maintaining normal cell homeostasis. However, their role and underlying mechanisms in ICH-induced secondary brain injury (SBI) have yet to be elucidated.MethodsWe established an ICH model using male Sprague-Dawley (SD) rats by injecting autologous arterial blood into the unilateral basal ganglia. To establish ICH modelin vitro, oxyhemoglobin (OxyHb; 20 μM) and neurons were cultured for 6 h at 37 °C, 5% CO2atmosphere. To investigate the role of WNK3 and the WNK3/SPAK/NKCC1 signaling pathway in SBI, after genetic interventions, rotation and water maze test, brain edema and neuroinflammation were detected, and terminal-deoxynucleoitidyl transferase mediated dUTP nick end labeling (TUNEL), Fluoro-Jade C (FJC), and Nissl staining were performed.ResultsOur data showed that WNK3 expression in brain tissue were upregulated after ICH induction. In addition, silencing of WNK3 reduced neuronal apoptosis, and inflammatory responses in rats that underwent ICH. Inhibition of WNK3 expression reduced the damaged blood-brain barrier (BBB), alleviated the impaired degree of cerebral edema, and improved disruptive neurobehavioral cognition caused by ICH. Moreover, overexpression of WNK3 had the opposite effects. Finally, WNK3/SPAK/NKCC1 signaling pathway may be involved in the above-mentioned processes.ConclusionsIn conclusion, our findings showed that WNK3 and WNK3/SPAK/NKCC1 signaling pathway play a vital biological function in ICH-induced SBI. Depletion of WNK3 attenuated brain injury after ICH bothin vivoandin vitro. Thus, WNK3 and WNK3/SPAK/NKCC1 signaling pathway are potential targets for treating SBI after ICH.
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