Overexpression of the neuronal human (Pro)renin receptor mediates angiotensin ii-independent blood pressure regulation in the central nervous system

Hua Peng, Dane D. Jensen, Wencheng Li, Michelle N. Sullivan, Sophie A. Buller, Caleb J. Worker, Silvana G. Cooper, Shiqi Zheng, Scott Earley, Curt D. Sigmund, Yumei Feng

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)H580-H592
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume314
Issue number3
DOIs
StatePublished - Apr 2018

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Keywords

  • (pro)renin receptor
  • Central nervous system
  • NADPH oxidase
  • Neurogenic hypertension
  • Renin angiotensin system

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Peng, H., Jensen, D. D., Li, W., Sullivan, M. N., Buller, S. A., Worker, C. J., Cooper, S. G., Zheng, S., Earley, S., Sigmund, C. D., & Feng, Y. (2018). Overexpression of the neuronal human (Pro)renin receptor mediates angiotensin ii-independent blood pressure regulation in the central nervous system. American Journal of Physiology - Heart and Circulatory Physiology, 314(3), H580-H592. https://doi.org/10.1152/ajpheart.00310.2017