Faculty Collaboration Database

Overexpression of the neuronal human (pro)renin receptor mediates angiotensin II-independent blood pressure regulation in the central nervous system. Am J Physiol Heart Circ Physiol 2018 Mar 01;314(3):H580-H592

Date

01/20/2018

Pubmed ID

29350998

Pubmed Central ID

PMC5899258

DOI

10.1152/ajpheart.00310.2017

Scopus ID

2-s2.0-85045437910 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

Despite advances in antihypertensive therapeutics, at least 15-20% of hypertensive patients have resistant hypertension through mechanisms that remain poorly understood. In this study, we provide a new mechanism for the regulation of blood pressure (BP) in the central nervous system (CNS) by the (pro)renin receptor (PRR), a recently identified component of the renin-angiotensin system that mediates ANG II formation in the CNS. Although PRR also mediates ANG II-independent signaling, the importance of these pathways in BP regulation is unknown. Here, we developed a unique transgenic mouse model overexpressing human PRR (hPRR) specifically in neurons (Syn-hPRR). Intracerebroventricular infusion of human prorenin caused increased BP in Syn-hPRR mice. This BP response was attenuated by a NADPH oxidase (NOX) inhibitor but not by antihypertensive agents that target the renin-angiotensin system. Using a brain-targeted genetic knockdown approach, we found that NOX4 was the key isoform responsible for the prorenin-induced elevation of BP in Syn-hPRR mice. Moreover, inhibition of ERK significantly attenuated the increase in NOX activity and BP induced by human prorenin. Collectively, our findings indicate that an ANG II-independent, PRR-mediated signaling pathway regulates BP in the CNS by a PRR-ERK-NOX4 mechanism. NEW & NOTEWORTHY This study characterizes a new transgenic mouse model with overexpression of the human (pro)renin receptor in neurons and demonstrated a novel angiotensin II-independent mechanism mediated by human prorenin and the (pro)renin receptor in the central regulation of blood pressure.

Author List

Peng H, Jensen DD, Li W, Sullivan MN, Buller SA, Worker CJ, Cooper SG, Zheng S, Earley S, Sigmund CD, Feng Y

Author

Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin II
Animals
Blood Pressure
Central Nervous System
Disease Models, Animal
Extracellular Signal-Regulated MAP Kinases
Female
Humans
Hypertension
Infusions, Intraventricular
Male
Mice, Inbred C57BL
Mice, Transgenic
NADPH Oxidase 4
Neurons
Promoter Regions, Genetic
Receptors, Cell Surface
Renin
Renin-Angiotensin System
Signal Transduction
Synapsins
Up-Regulation
Vacuolar Proton-Translocating ATPases