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J Am Soc Nephrol. 2015 Dec;26(12):2953-62. doi: 10.1681/ASN.2014080816. Epub 2015 Apr 8.

Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion.

Author information

1
Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina;
2
Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina; Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany;
3
Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; and.
4
Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina; Cardiovascular and Metabolic Disorders Research Program, Duke-National University of Singapore, Graduate Medical School, Singapore tcoffman@duke.edu.

Abstract

Inappropriate activation of the type 1A angiotensin (AT1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)-dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely preserved (approximately 80% of control levels) in SMKO mice because of exaggerated activity of the sympathetic nervous system rather than residual actions of AT1B receptors. In contrast, Ang II-dependent responses in the renal circulation were almost completely eliminated in SMKO mice (approximately 5%-10% of control levels). These findings suggest that direct actions of AT1A receptors in VSMCs are essential for regulation of renal blood flow by Ang II and highlight the capacity of Ang II-dependent vascular responses in the kidney to effect natriuresis and BP control.

KEYWORDS:

angiotensin; blood pressure; renal hemodynamics; vascular

PMID:
25855778
PMCID:
PMC4657834
DOI:
10.1681/ASN.2014080816
[Indexed for MEDLINE]
Free PMC Article

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