Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive Hypertension

  • Biomolecules. 2022 Aug 24;12(9):1169. doi: 10.3390/biom12091169.
Silvana G Cooper  1  2 ,  Lucas A C Souza  1  2 ,  Caleb J Worker  1  2 ,  Ariana Julia B Gayban  1  2 ,  Sophie Buller  3 ,  Ryosuke Satou  4 ,  Yumei Feng Earley  1  2
Affiliations
  • 1. Departments of Pharmacology, and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USA.
  • 2. Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, NV 89557, USA.
  • 3. MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 1TN, UK.
  • 4. Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
PMID: 36139008 DOI: 10.3390/biom12091169
Abstract

The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance of renin-b in cardiovascular and metabolic regulation. However, the role of endogenous brain prorenin in the development of salt-sensitive Hypertension remains undefined. In this study, we test the hypothesis that renin-a produced locally in the brain contributes to the pathogenesis of Hypertension. Using RNAscope, we report for the first time that Renin mRNA is expressed in the subfornical organ (SFO), where it is found in glutamatergic and GABAergic neurons. Notably, we found that Renin mRNA was significantly elevated in the SFO and PVN in a mouse model of DOCA-salt-induced Hypertension. To examine the functional importance of renin-a in the SFO, we selectively ablated renin-a in the SFO in renin-a-floxed mice using a Cre-lox strategy. Importantly, renin-a ablation in the SFO attenuated the maintenance of DOCA-salt-induced Hypertension and improved autonomic function without affecting fluid or sodium intake. Molecularly, ablation of renin-a prevented the DOCA-salt-induced elevation in NADPH Oxidase 2 (NOX2) in the SFO without affecting NOX4 or angiotensin II type 1 and 2 receptors. Collectively, our findings demonstrate that endogenous renin-a within the SFO is important for the pathogenesis of salt-sensitive Hypertension.

Keywords
NAD(P)H oxidase; angiotensin receptor; autonomic control; renin-angiotensin system; salt-sensitive hypertension.