Mutagenesis of the Cleavage Site of Pro Renin Receptor Abrogates Angiotensin II-Induced Hypertension in Mice. Issue 1 (24th May 2021)

• Record Type: Journal Article
• Authors: Wang, Fei; Chen, Yanting; Zou, Chang-Jiang; Luo, Renfei; Yang, Tianxin
• Is Part Of: Hypertension. Volume 78:Issue 1(2021)
• Page Start: 115
• Page End: 127
• Publication Date: 2021-05-24
• Subjects: angiotensin II -- hypertension -- renin-angiotensin system site-1 protease -- soluble (pro)renin receptor; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.121.16770
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : Supplemental Digital Content is available in the text. Abstract : It is well demonstrated that activation of renal PRR ([pro]renin receptor) contributes to AngII (angiotensin II)-induced hypertension. Relatively, less is known for the function of sPRR (soluble PRR), the extracellular domain of PRR, primarily generated by S1P (site-1 protease) and furin. Moreover, the relationship between PRR/sPRR and the renin-angiotensin system (RAS) has been debated. In the present study, we used CRISPR/Cas9 strategy to generate mice with mutagenesis of the overlapping cleavage site for both proteases in PRR (termed as PRR R279V/L282V ) to examine the phenotype during AngII infusion with particular emphasis on circulating and intrarenal renin status. PRR R279V/L282V mice exhibited a reduction of sPRR level in plasma by ≈53% and in the kidney by ≈82%, were fertile, and had no gross developmental abnormalities. At basal condition, PRR R279V/L282V mice had drastically suppressed renin levels from plasma, urine, and the kidney as compared to wild-type controls. The hypertensive response of PRR R279V/L282V to AngII infusion was blunted in parallel with attenuated response of intrarenal renin and renal medullary α-epithelial sodium channel expression. By using Ussing chamber technique, primary collecting duct cells from PRR R279V/L282V mice exhibited blunted response of epithelial sodium channel activity to AngII as compared to wild-type cells. Together, these results represent strong evidence favoring sPRR as a mediator of AngII-induced hypertension and a master regulator of renin expression. Therefore, PRR should be considered as an integrative member of the RAS.