Exploring type I angiotensin (AT<sub>1</sub>) receptor functions through gene targeting

Crowley, Steven D.; Tharaux, Pierre‐Louis; Audoly, Laurent; Coffman, Thomas M.

doi:10.1111/j.1365-201x.2004.01331.x

Cited by 49 publications

(48 citation statements)

References 85 publications

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“…Kidney transplantation was carried out between genetically matched F 1 (C57BL͞6 ϫ 129) wild-type mice and F 1 (C57BL͞6 ϫ 129) mice homozygous for a targeted disruption of the Agtr1a gene locus encoding the AT 1A receptor (14). The AT 1A receptor is the major AT 1 receptor isoform in the mouse and the closest mouse homologue to the human AT 1 receptor gene (12).…”

Section: Resultsmentioning

confidence: 99%

“…The effects of Ang II to increase blood pressure are mediated by AT 1 receptors (12), and these receptors are expressed in a variety of organ systems thought to play key roles in blood pressure homeostasis, including the heart, kidney, blood vessels, adrenal glands, and cardiovascular control centers in the brain (13). For example, in the vascular system, stimulation of AT 1 receptors causes potent vasoconstriction (14,15).…”

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confidence: 99%

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Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Crowley

Gurley

Herrera

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

617

542

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Essential hypertension is a common disease, yet its pathogenesis is not well understood. Altered control of sodium excretion in the kidney may be a key causative feature, but this has been difficult to test experimentally, and recent studies have challenged this hypothesis. Based on the critical role of the renin-angiotensin system (RAS) and the type I (AT 1) angiotensin receptor in essential hypertension, we developed an experimental model to separate AT 1 receptor pools in the kidney from those in all other tissues. Although actions of the RAS in a variety of target organs have the potential to promote high blood pressure and end-organ damage, we show here that angiotensin II causes hypertension primarily through effects on AT 1 receptors in the kidney. We find that renal AT1 receptors are absolutely required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. When AT 1 receptors are eliminated from the kidney, the residual repertoire of systemic, extrarenal AT1 receptors is not sufficient to induce hypertension or cardiac hypertrophy. Our findings demonstrate the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications. Further, they suggest that the major mechanism of action of RAS inhibitors in hypertension is attenuation of angiotensin II effects in the kidney. transgenic mice ͉ kidney transplantation ͉ blood pressure H igh blood pressure (BP) is a highly prevalent disorder, and its complications (including heart disease, stroke, and kidney disease) are a major public health problem (1). Despite decades of scrutiny, the precise pathogenesis of essential hypertension has been difficult to delineate. Guyton and his associates suggested that defective handling of sodium by the kidney and consequent dysregulation of body fluid volumes is a requisite, final common pathway in hypertension pathogenesis (2). The powerful capacity of this pathway to modulate blood pressure is illustrated by the elegant studies of Lifton and associates showing that virtually all of the Mendelian disorders with major impact on blood pressure homeostasis are caused by genetic variants affecting salt and water reabsorption by the distal nephron (3). On the other hand, several recent studies have suggested that primary vascular defects may cause hypertension by impacting peripheral resistance without direct involvement of renal excretory functions (4-7).Among the various regulatory systems that impact blood pressure, the RAS has a key role. Inappropriate activation of the RAS, as in renal artery stenosis, leads to profound hypertension and cardiovascular morbidity (8). Moreover, in patients with essential hypertension who typically lack overt signs of RAS activation, ACE inhibitors and angiotensin receptor blockers (ARBs) effectively reduce blood pressure and ameliorate cardiovascular complications (9-11), suggesting that dysregulation of the RAS contributes to their elevated blood pressure.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Crowley

Gurley

Herrera

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

617

542

View full text Add to dashboard Cite

show abstract

“…The effects of Ang II occur via activation of two receptor subtypes, AT 1 and AT 2 (Hein, 1998;Crowley et al, 2004). The vasoconstrictor effects of Ang II are generally considered to result from activation of AT 1 receptors.…”

Section: Introductionmentioning

confidence: 99%

“…The vasoconstrictor effects of Ang II are generally considered to result from activation of AT 1 receptors. In rodents, two AT 1 receptor subtypes (AT 1A and AT 1B ) exist, but cannot be distinguished using pharmacological inhibitors (Hein, 1998;Crowley et al, 2004). Thus, our third goal was to use genetically altered mice deficient in expression of AT 1A receptors to examine the importance of the AT 1A receptor in mediating the vascular effects of Ang II.…”

Section: Introductionmentioning

confidence: 99%

Cerebral Vascular Effects of Angiotensin II: New Insights from Genetic Models

Faraci

Lamping

Modrick

et al. 2005

J Cereb Blood Flow Metab

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Very little is known regarding the mechanisms of action of angiotensin II (Ang II) or the consequences of Ang II-dependent hypertension in the cerebral circulation. We tested the hypothesis that Ang II produces constriction of cerebral arteries that is mediated by activation of AT 1A receptors and Rho-kinase. Basilar arteries (baseline diameter B130 lm) from mice were isolated, cannulated and pressurized to measure the vessel diameter. Angiotensin II was a potent constrictor in arteries from male, but not female, mice. Vasoconstriction in response to Ang II was prevented by an inhibitor of Rho-kinase (Y-27632) in control mice, and was reduced by B85% in mice deficient in expression of AT 1A receptors. We also examined the chronic effects of Ang II using a model of Ang II-dependent hypertension, mice which overexpress human renin (R þ ) and angiotensinogen (A þ ). Responses to the endothelium-dependent agonist acetylcholine were markedly impaired in R þ A þ mice (Po0.01) compared with controls, but were restored to normal by a superoxide scavenger (PEG-SOD). A-23187 (another endothelium-dependent agonist) produced vasodilation in control mice, but no response or vasoconstriction in R þ A þ mice. In contrast, dilation of the basilar artery in response to a NO donor (NONOate) was similar in R þ A þ mice and controls. Thus, Ang II produces potent constriction of cerebral arteries via activation of AT 1A receptors and Rho-kinase. There are marked gender differences in cerebral vascular responses to Ang II. Endothelial function is greatly impaired in a genetic model of Ang II-dependent hypertension via a mechanism that involves superoxide.

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“…In rodents, BP and the pathophysiological effects of RAS are primarily mediated by the AT1a receptor. 1 The role of RAS in the pathogenesis of cardiovascular endorgan damages has been well characterized. Interestingly, clinical studies and animal experiments have demonstrated that inhibition of RAS with pharmacological agents such as angiotensin-converting enzyme inhibitors and AT1 receptor blockers (ARBs), as well as genetic disruption of RAS signaling components, diminishes end-organ damage, particularly atherosclerosis [2][3][4] and kidney injury.…”

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confidence: 99%

Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells

Kato

Ishida

Nagano

et al. 2008

Laboratory Investigation

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The renin-angiotensin system (RAS) modulates end-organ damages, resulting in cardiovascular and kidney diseases. Experiments both in vitro and in vivo demonstrate that the angiotensin II (Ang II) type 1 (AT1) receptor pathway also exerts pro-inflammatory and pro-atherogenic effects on bone marrow-derived cells (BMDCs). Here, we investigated how AT1 receptor expression by BMDCs contributes to atherosclerosis and kidney injury in vivo by transplanting BM into RASactivated transgenic mice. There was no difference in the extent of kidney damage between mice receiving BM transplants from mutant mice lacking the angiotensin II type 1a receptor (AT1a) gene and mice receiving transplants from wild-type (WT) mice. However, mice receiving transplants from AT1a 'knockout' (KO) mice displayed accelerated lethality and atherosclerotic lesions. These results indicated that the effects of AT1a receptor on BMDCs are organ dependent. Microarray expression profiling of macrophages from AT1a-KO mice revealed significant changes in the mRNA levels for a number of genes implicated in atherosclerosis. In accordance with the in vivo atherosclerosis results, AT1a-KO macrophages exhibited greater uptake of modified lipoproteins relative to macrophages from WT mice. We propose that the expression of AT1a receptor by BMDCs limits atherosclerosis in vivo.

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Exploring type I angiotensin (AT₁) receptor functions through gene targeting

Cited by 49 publications

References 85 publications

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Cerebral Vascular Effects of Angiotensin II: New Insights from Genetic Models

Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells

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Exploring type I angiotensin (AT1) receptor functions through gene targeting

Cited by 49 publications

References 85 publications

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Cerebral Vascular Effects of Angiotensin II: New Insights from Genetic Models

Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells

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Exploring type I angiotensin (AT₁) receptor functions through gene targeting