Inactivation of Cys674 in SERCA2 increases BP by inducing endoplasmic reticulum stress and soluble epoxide hydrolase
Inactivation of Cys674 in SERCA2 increases BP by inducing endoplasmic reticulum stress and soluble epoxide hydrolase
复制标题
SERCA2 半胱氨酸 674 失活可通过诱导内质网应激和可溶性环氧化物水解酶来升高血压。
DOI：
10.1111/bph.14937
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发表时间：
2020-01-30
影响因子：
7.3
通讯作者：
Tong, Xiaoyong
中科院分区：
文献类型：
--
作者：
Liu, Gang;Wu, Fuhua;Tong, Xiaoyong
背景和目的肾脏在调节钠稳态和血压方面起着至关重要的作用。高血压小鼠肾皮质肌浆/内质网钙ATPase 2(SERCA2)中Cys(674)(C674)的不可逆氧化增加。C674失活是否会促进高血压尚不清楚。在这里，我们研究了C674失活对血压的影响，以及它在肾脏中的作用。实验方法我们使用杂合子SERCA2 C674S敲入(SKI)小鼠，其中C674的一半被丝氨酸取代，以代表C674的部分不可逆氧化。测定了SKI小鼠及其产仔野生型(WT)小鼠的血压、尿量和尿液成分。收集肾脏进行细胞培养、Na+/K+-ATPase活性、蛋白表达和免疫组织学分析。结果与WT小鼠相比，SKI小鼠血压升高，尿量和钠排泄减少，内质网(ER)应激标志物和可溶性环氧化物水解酶(SEH)表达上调，肾皮质和肾近端小管细胞多巴胺D-1受体表达下调。内质网应激与sEH相互调节，均位于D-1受体的上游。抑制内质网应激或sEH可上调SKI小鼠D-1受体表达，降低Na+/K+-ATPase活性，增加钠排泄，降低血压。结论SERCA2C674失活通过诱导内质网应激和sEH促进高血压的发展。我们的研究强调了C674氧化还原状态在血压控制中的重要性，以及SERCA2对肾脏钠稳态和血压的贡献。
Background and Purpose The kidney is essential in regulating sodium homeostasis and BP. The irreversible oxidation of Cys(674) (C674) in the sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) is increased in the renal cortex of hypertensive mice. Whether inactivation of C674 promotes hypertension is unclear. Here we have investigated the effects on BP of the inactivation of C674, and its role in the kidney. Experimental Approach We used heterozygous SERCA2 C674S knock-in (SKI) mice, where half of C674 was substituted by serine, to represent partial irreversible oxidation of C674. The BP, urine volume, and urine composition of SKI mice and their littermate wild-type (WT) mice were measured. The kidneys were collected for cell culture, Na+/K+-ATPase activity, protein expression, and immunohistological analysis. Key Results Compared with WT mice, SKI mice had higher BP, lower urine volume and sodium excretion, up-regulated endoplasmic reticulum (ER) stress markers and soluble epoxide hydrolase (sEH), and down-regulated dopamine D-1 receptors in renal cortex and cells from renal proximal tubule. ER stress and sEH were mutually regulated, and both upstream of D-1 receptors. Inhibition of ER stress or sEH up-regulated expression of D-1 receptors, decreased the activity of Na+/K+-ATPase, increased sodium excretion, and lowered BP in SKI mice. Conclusions and Implications The inactivation of SERCA2 C674 promotes the development of hypertension by inducing ER stress and sEH. Our study highlights the importance of C674 redox status in BP control and the contribution of SERCA2 to sodium homeostasis and BP in the kidney.