Stimulation of Epithelial Sodium Channels in Endothelial Cells by Bone Morphogenetic Protein-4 Contributes to Salt-Sensitive Hypertension in Rats

• Type of Material: Article
• Authors: Xu Yang, Harbin Medical University; Na Niu, Harbin Medical University; Chen Liang, Harbin Medical University; Ming-Ming Wu, Harbin Medical University; Liang-Liang Tang, Harbin Medical University; Qiu-Shi Wang, Emory University; Jie Lou, Harbin Medical University; Bin-Lin Song, Harbin Medical University; Wei Zheng, Emory University; He-Ping Ma, Emory University; Zhi-Ren Zhang, Harbin Medical University
• Language: English
• Date: 2020-10-28
• Publisher: HINDAWI LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Xu Yang et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1155/2020/3921897
• Title of Journal or Parent Work: OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
• Volume: 2020
• Start Page: 3921897
• End Page: 3921897
• Grant/Funding Information: This work was generously supported by grants from the National Natural Science Foundation of China (Nos. 81930009, 91639202, 81870370 to Z.Z.), National Institutes of Health (NIH) (R01 DK 100582 to H. M.), and Postgraduate Research & Practice Innovation Program of Harbin Medical University (YJSCX2017-65HYD to X.Y.). The study was also supported by the Nn10 program of Harbin Medical University Cancer Hospital.
• Keywords: SYSTEM; INHIBITION; EXPRESSION; PROLIFERATION; ALDOSTERONE; DIETARY SALT; Science & Technology; VASCULAR ENDOTHELIUM; Life Sciences & Biomedicine; DYSFUNCTION; STIFFENS; SGK1; Cell Biology
• Research Categories: Health Sciences, Nutrition

Abstract

Previous studies have shown that high salt induces artery stiffness by causing endothelial dysfunction via increased sodium influx. We used our unique split-open artery technique combined with protein biochemistry and in vitro measurement of vascular tone to test a hypothesis that bone morphogenetic protein 4 (BMP4) mediates high salt-induced loss of vascular relaxation by stimulating the epithelial sodium channel (ENaC) in endothelial cells. The data show that high salt intake increased BMP4 both in endothelial cells and in the serum and that exogenous BMP4 stimulated ENaC in endothelial cells. The data also show that the stimulation is mediated by p38 mitogen-activated protein kinases (p38 MAPK) and serum and glucocorticoid-regulated kinase 1 (Sgk1)/neural precursor cell expressed developmentally downregulated gene 4-2 (Nedd4-2) (Sgk1/Nedd4-2). Furthermore, BMP4 decreased mesenteric artery relaxation in a benzamil-sensitive manner. These results suggest that high salt intake stimulates endothelial cells to express and release BMP4 and that the released BMP4 reduces artery relaxation by stimulating ENaC in endothelial cells. Therefore, stimulation of ENaC in endothelial cells by BMP4 may serve as another pathway to participate in the complex mechanism of salt-sensitive (SS) hypertension.