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Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.

Authors
  • Li, Wencheng1
  • Sullivan, Michelle N1
  • Zhang, Sheng1
  • Worker, Caleb J1
  • Xiong, Zhenggang1
  • Speth, Robert C1
  • Feng, Yumei2
  • 1 From the Department of Biomedical Sciences, Center for Cardiovascular Research, Colorado State University, Fort Collins (W.L., M.N.S., C.J.W., Y.F.); Department of Physiology, Tulane Hypertension and Renal Center of Excellence (S.Z.), and Department of Pathology and Laboratory Medicine (Z.X.), Tulane University School of Medicine, New Orleans, LA; and Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL (R.C.S.).
  • 2 From the Department of Biomedical Sciences, Center for Cardiovascular Research, Colorado State University, Fort Collins (W.L., M.N.S., C.J.W., Y.F.); Department of Physiology, Tulane Hypertension and Renal Center of Excellence (S.Z.), and Department of Pathology and Laboratory Medicine (Z.X.), Tulane University School of Medicine, New Orleans, LA; and Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL (R.C.S.). [email protected]
Type
Published Article
Journal
Hypertension (Dallas, Tex. : 1979)
Publication Date
Feb 01, 2015
Volume
65
Issue
2
Pages
352–361
Identifiers
DOI: 10.1161/HYPERTENSIONAHA.114.04458
PMID: 25421983
Source
Medline
Keywords
License
Unknown

Abstract

We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension.

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