SERCA2 dysfunction triggers hypertension by interrupting mitochondrial homeostasis and provoking oxidative stress

作者全名："Wang, Yaping; Wang, Min; Su, Hang; Song, Jiarou; Ren, Minghua; Hu, Pingping; Liu, Gang; Tong, Xiaoyong"

作者地址："[Wang, Yaping; Wang, Min; Song, Jiarou; Tong, Xiaoyong] Chongqing Univ, Innovat Drug Res Ctr, Chongqing 401331, Peoples R China; [Su, Hang] Zunyi Med Univ, Affiliated Hosp, Zunyi 563000, Guizhou, Peoples R China; [Ren, Minghua] Harbin Med Univ, Affiliated Hosp 1, Dept Urinary Surg, Harbin 150001, Heilongjiang, Peoples R China; [Hu, Pingping] Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China; [Liu, Gang] Xinxiang Med Univ, Coll Basic Med Sci, Henan Key Lab Med Tissue Regenerat, Xinxiang 453003, Henan, Peoples R China; [Tong, Xiaoyong] Jinfeng Lab, Chongqing 401329, Peoples R China; [Liu, Gang] Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, 55 Daxuecheng South Rd, Chongqing 401331, Peoples R China; [Tong, Xiaoyong] Xinxiang Med Univ, Sch Basic Med Sci, Henan Key Lab Med Tissue Regenerat, 601 Jinsui Ave, Xinxiang 453003, Henan, Peoples R China"

通信作者："Liu, G (通讯作者)，Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, 55 Daxuecheng South Rd, Chongqing 401331, Peoples R China.; Tong, XY (通讯作者)，Xinxiang Med Univ, Sch Basic Med Sci, Henan Key Lab Med Tissue Regenerat, 601 Jinsui Ave, Xinxiang 453003, Henan, Peoples R China."

来源：FREE RADICAL BIOLOGY AND MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001154513900001

JCR分区：Q1

影响因子：7.1

年份：2024

卷号：212

期号：　

开始页：284

结束页：294

文献类型：Article; Early Access

关键词：SERCA2; Hypertension; Oxidant stress; Mitochondrial dysfunction; Water-sodium retention

摘要："Background and aim: Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is critical in maintaining Ca2+ homeostasis. The cysteine 674 (C674) is the key redox regulatory cysteine in regulating SERCA2 activity, which is irreversibly oxidized in the renal cortex of hypertensive mice. We have reported that the substitution of C674 by serine causes SERCA2 dysfunction and increases blood pressure by induction of endoplasmic reticulum stress (ERS). This study is to explore whether the dysfunction of SERCA2 causes hypertension by interrupting mitochondrial homeostasis and inducing oxidative stress. Methods & results: We used heterozygous SERCA2 C674S gene mutation knock-in (SKI) mice, where one copy of C674 was substituted by serine to represent partial C674 oxidation. In renal proximal tubule (RPT) cells, the substitution of C674 by serine decreased mitochondrial Ca2+ content, increased mitochondrial membrane potential, ATP content, and reactive oxygen species (ROS), which could be reversed by ERS inhibitor 4-phenylbutyric acid or SERCA2 agonist CDN1163. In SKI RPT cells, the redox modulator Tempol alleviated oxidative stress, downregulated the protein expression of ERS markers and soluble epoxide hydrolase, upregulated the protein expression of dopamine D1 receptor, and reduced Na+/K+- ATPase activity. In SKI mice, SERCA2 agonists CDN1163 and [6]-Gingerol, or the redox modulator Tempol increased urine output and lowered blood pressure. Conclusion: The irreversible oxidation of C674 is not only an indicator of increased ROS, but also further inducing oxidative stress to cause hypertension. Activation of SERCA2 or inhibition of oxidative stress is beneficial to alleviate hypertension caused by SERCA2 dysfunction."

基金机构："National Natural Science Foundation of China [31571172, 81870343, 81700237]; Chongqing Natural Science Foundation [cstc2021jcyj-msxmX0043]; Henan Provincial Science and Technology R D Plan Project [222102310248]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (31571172 and 81870343, X.T., and 81700237, P.H.) , Chongqing Natural Science Foundation (cstc2021jcyj-msxmX0043, X. T.) , Henan Provincial Science and Technology R & D Plan Project (222102310248, G.L.) ."