Increased Susceptibility of Mice Lacking Renin-b to Angiotensin II–Induced Organ Damage

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 76; no. 2; pp. 468 - 477
• Main Authors: Nakagawa, Pablo, Nair, Anand R., Agbor, Larry N., Gomez, Javier, Wu, Jing, Zhang, Shao Yang, Lu, Ko-Ting, Morgan, Donald A., Rahmouni, Kamal, Grobe, Justin L., Sigmund, Curt D.
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01-08-2020
• Subjects: Angiotensin II; Animals; Blood Pressure - physiology; Genetic Predisposition to Disease; Hypertension - chemically induced; Hypertension - genetics; Hypertension - metabolism; Kidney - metabolism; Male; Mice; Mice, Knockout; Protein Isoforms - genetics; Protein Isoforms - metabolism; Renin - blood; Renin - genetics; Renin - metabolism; Renin-Angiotensin System - physiology; blood pressure; aldosterone; angiotensin II; exons; renin; heart; renin-angiotensin system
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.120.14972

Several cardiac and renal diseases are attributed to a dysregulation of the renin-angiotensin system. Renin, the rate-limiting enzyme of the renin-angiotensin system, has 2 isoforms. The classical renin isoform (renin-a) encoding preprorenin is mainly confined to the juxtaglomerular cells and released into the circulation upon stimulation. Alternatively, renin-b is predicted to remain intracellular and is expressed in the brain, heart, and adrenal gland. In the brain, ablation of renin-b (Ren-bNull mice) results in increased brain renin-angiotensin system activity. However, the consequences of renin-b ablation in tissues outside the brain remain unknown. Therefore, we hypothesized that renin-b protects from hypertensive cardiac and renal end-organ damage in mice. Ren-bNull mice exhibited normal blood pressure at baseline. Thus, we induced hypertension by using a slow pressor dose of Ang II (angiotensin II). Ang II increased blood pressure in both wild type and Ren-bNull to the same degree. Although the blood pressure between Ren-bNull and wild-type mice was elevated equally, 4-week infusion of Ang II resulted in exacerbated cardiac remodeling in Ren-bNull mice compared with wild type. Ren-bNull mice also exhibited a modest increase in renal glomerular matrix deposition, elevated plasma aldosterone, and a modestly enhanced dipsogenic response to Ang II. Interestingly, ablation of renin-b strongly suppressed plasma renin, but renal cortical renin mRNA was preserved. Altogether, these data indicate that renin-b might play a protective role in the heart, and thus renin-b could be a potential target to treat hypertensive heart disease.