Angiotensin II regulates brain (pro)renin receptor expression through activation of cAMP response element-binding protein

Document Type

Article

Abstract

We reported that brain (pro)renin receptor (PRR) expression levels are elevated in DOCA-salt-induced hypertension; however, the underlying mechanism remained unknown. To address whether ANG II type 1 receptor (AT1R) signaling is involved in this regulation, we implanted a DOCA pellet and supplied 0.9% saline as the drinking solution to C57BL/6J mice. Sham pellet-implanted mice that were provided regular drinking water served as controls. Concurrently, mice were intracerebroventricularly infused with the AT1R blocker losartan, angiotensin-converting-enzyme inhibitor captopril, or artificial cerebrospinal fluid for 3 wk. Intracerebroventricular infusion of losartan or captopril attenuated DOCA-salt-induced PRR mRNA elevation in the paraventricular nucleus of the hypothalamus, suggesting a role for ANG II/AT1R signaling in regulating PRR expression during DOCA-salt hypertension. To test which ANG II/AT1R downstream transcription factors were involved in PRR regulation, we treated Neuro-2A cells with ANG II with or without CREB (cAMP response element-binding protein) or AP-1 (activator protein-1) inhibitors, or CREB siRNA. CREB and AP-1 inhibitors, as well as CREB knockdown abolished ANG II-induced increases in PRR levels. ANG II also induced PRR upregulation in primary cultured neurons. Chromatin immunoprecipitation assays revealed that ANG II treatment increased CREB binding to the endogenous PRR promoter in both cultured neurons and hypothalamic tissues of DOCA-salt hypertensive mice. This increase in CREB activity was reversed by AT1R blockade. Collectively, these findings indicate that ANG II acts via AT1R to upregulate PRR expression both in cultured cells and in DOCA-salt hypertensive mice by increasing CREB binding to the PRR promoter.

Keywords

(pro)renin receptor, CAMP response element-binding protein, central nervous system, renin-angiotensin system, salt-sensitive hypertension

Medical Subject Headings

Angiotensin II (metabolism); Angiotensin II Type 1 Receptor Blockers (administration & dosage); Angiotensin-Converting Enzyme Inhibitors (administration & dosage); Animals; Binding Sites; CREB-Binding Protein (genetics, metabolism); Cell Line; Desoxycorticosterone Acetate; Disease Models, Animal; Hypertension (chemically induced, drug therapy, genetics, metabolism); Infusions, Intraventricular; Mice, Inbred C57BL; Paraventricular Hypothalamic Nucleus (drug effects, metabolism); Phosphorylation; Promoter Regions, Genetic; Proton-Translocating ATPases (genetics, metabolism); RNA Interference; RNA, Messenger (metabolism); Receptor, Angiotensin, Type 1 (drug effects, metabolism); Receptors, Cell Surface (genetics, metabolism); Renin-Angiotensin System (drug effects); Signal Transduction; Sodium Chloride; Time Factors; Transcription Factor AP-1 (metabolism); Transfection; Up-Regulation; Prorenin Receptor

Publication Date

7-15-2015

Publication Title

American journal of physiology. Regulatory, integrative and comparative physiology

E-ISSN

1522-1490

Volume

309

Issue

2

First Page

R138

Last Page

47

PubMed ID

25994957

Digital Object Identifier (DOI)

10.1152/ajpregu.00319.2014

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