1. Academic Validation
  2. Soluble (pro)renin receptor induces endothelial dysfunction and hypertension in mice with diet-induced obesity via activation of angiotensin II type 1 receptor

Soluble (pro)renin receptor induces endothelial dysfunction and hypertension in mice with diet-induced obesity via activation of angiotensin II type 1 receptor

  • Clin Sci (Lond). 2021 Mar 26;135(6):793-810. doi: 10.1042/CS20201047.
Ziwei Fu 1 Fei Wang 2 Xiyang Liu 1 Jiajia Hu 1 Jiahui Su 1 Xiaohan Lu 2 Aihua Lu 1 Jae Min Cho 3 4 J David Symons 3 4 Chang-Jiang Zou 2 Tianxin Yang 2
Affiliations

Affiliations

  • 1 Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
  • 2 Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, U.S.A.
  • 3 Department of Nutrition and Integrative Physiology, University of Utah School of Medicine, Salt Lake City, Utah, U.S.A.
  • 4 Division of Endocrinology, Metabolism, and Diabetes, Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, Utah, U.S.A.
Abstract

Until now, renin-angiotensin system (Ras) hyperactivity was largely thought to result from angiotensin II (Ang II)-dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)Renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)Renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, Apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure.

Keywords

Angiotensin II type 1 receptor; endothelial dysfunction; hypertension; soluble (pro)renin receptor.

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