Losartan prevents the elevation of blood pressure in adipose-PRR deficient female mice while elevated circulating sPRR activates the renin-angiotensin system

Am J Physiol Heart Circ Physiol. 2019 Mar 1;316(3):H506-H515. doi: 10.1152/ajpheart.00473.2018. Epub 2018 Dec 14.

Abstract

Deletion of the prorenin receptor (PRR) in adipose tissue elevates systolic blood pressure (SBP) and the circulating soluble form of PRR (sPRR) in male mice fed a high-fat (HF) diet. However, sex differences in the contribution of adipose-PRR and sPRR to the regulation of the renin-angiotensin system (RAS) in key organs for blood pressure control are undefined. Therefore, we assessed blood pressure and the systemic and intrarenal RAS status in adipose-PRR knockout (KO) female mice. Blockade of RAS with losartan blunted SBP elevation in HF diet-fed adipose-PRR KO mice. ANG II levels were significantly increased in the renal cortex of HF diet-fed adipose-PRR KO female mice, but not systemically. HF diet-fed adipose-PRR KO mice exhibited higher vasopressin levels, water retention, and lower urine output than wild-type (WT) mice. The results also showed that deletion of adipose-PRR increased circulating sPRR and total hepatic sPRR contents, suggesting the liver as a major source of elevated plasma sPRR in adipose-PRR KO mice. To mimic the elevation of circulating sPRR and define the direct contribution of systemic sPRR to the regulation of the RAS and vasopressin, C57BL/6 female mice fed a standard diet were infused with recombinant sPRR. sPRR infusion increased plasma renin levels, renal and hepatic angiotensinogen expression, and vasopressin. Together, these results demonstrate that the deletion of adipose-PRR induced an elevation of SBP likely mediated by an intrarenal ANG II-dependent mechanism and that sPRR participates in RAS regulation and body fluid homeostasis via its capacity to activate the RAS and increase vasopressin levels. NEW & NOTEWORTHY The elevation of systolic blood pressure appears to be primarily mediated by cortical ANG II in high-fat diet-fed adipose-prorenin receptor knockout female mice. In addition, our data support a role for soluble prorenin receptor in renin-angiotensin system activation and vasopressin regulation.

Keywords: adipose tissue; hypertension; prorenin receptor; soluble prorenin receptor; vasopressin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects*
  • Adipose Tissue / metabolism
  • Angiotensin II / blood
  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensinogen / genetics
  • Angiotensinogen / metabolism
  • Animals
  • Antihypertensive Agents / pharmacology*
  • Blood Pressure*
  • Female
  • Kidney / drug effects
  • Kidney / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Losartan / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Cell Surface / blood*
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / genetics
  • Renin-Angiotensin System*
  • Vasopressins / pharmacology

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Antihypertensive Agents
  • Receptors, Cell Surface
  • prorenin receptor
  • Vasopressins
  • Angiotensinogen
  • Angiotensin II
  • Losartan