Angiotensin II responses in AT1A receptor-deficient mice: a role for AT1B receptors in blood pressure regulation

Oliverio, Michael I.; Best, Christopher F.; Kim, Hyung Suk; Arendshorst, William J.; Smithies, Oliver; Coffman, Thomas M.

doi:10.1152/ajprenal.1997.272.4.f515

Cited by 122 publications

(158 citation statements)

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“…Moreover, renin null mice exhibit a 32 mm Hg decrease in blood pressure. The renin null phenotype is consistent with the null phenotype of other RAS genes (1)(2)(3)34). Therefore it is likely that the KE-null is a renin-hypomorph and not a renin-null thus supporting our conclusion.…”

Section: Discussionsupporting

confidence: 88%

The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

Zhoux

Davis

2006

Journal of Biological Chemistry

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Renin is the rate-limiting enzyme in the renin-angiotensin system and thus dictates the level of the pressor hormone angiotensin-II. The classical site of renin expression and secretion is the renal juxtaglomerular cell, where its expression is tightly regulated by physiological cues. An evolutionarily conserved transcriptional enhancer located 11 kb upstream of the human RENIN gene has been reported to markedly enhance transcription in renin expressing cells in vitro. However, its importance in vivo remains unclear. We tested whether this enhancer is required for appropriate tissue-and cell-specific expression, or for physiological regulation of the human RENIN gene. To accomplish this, we used a retrofitting technique employing homologous recombination in bacteria to delete the enhancer from a 160-kb P1-artificial chromosome containing human RENIN, two upstream genes and one downstream gene, and then generated two lines of transgenic mice. We previously showed that human renin expression in transgenic mice containing the wild type construct is tightly regulated as is expression of the linked genes. Deletion of the enhancer had no effect on tissue-specific expression of human RENIN, but using the downstream gene as an internal control, found that human RENIN mRNA levels were 3-10-fold decreased compared with constructs containing the enhancer. Despite this decrease in expression, renin protein remained localized to renal juxtaglomerular cells and was appropriately regulated by cues that either increase or decrease expression of renin. Our results suggest that sequences other than the enhancer may be necessary for tissue-specific, cell-specific, and regulated expression of human RENIN.Renin is the first and rate-limiting aspartyl protease in the renin-angiotensin system (RAS) 2 cascade that leads to the production of angiotensin-II (Ang-II) by the consecutive cleavage of angiotensinogen by renin and angiotensin-I by angiotensin converting enzyme. Ang-II is an important regulator of cardiovascular function, stimulating vasoconstriction, cardiac output, aldosterone synthesis, and sympathetic activity, thereby directly and indirectly enhancing peripheral vascular resistance and renal tubular water and salt reabsorption. The critical importance of the RAS is evidenced by gene targeted ablation of the RAS genes in mice. The elimination of any RAS gene in mice causes cardiovascular consequences that include hypotension and renal insufficiency, and developmental consequences including postnatal lethality (1-4). The cardiovascular and developmental defects can be complemented in mice by substitution of the mouse RAS with their human orthologs (5) or by targeted expression of Ang-II (6). In humans, genetic defects in the RAS were reported to cause renal tubular dysgenesis, hypotension, and early stillbirth (7). Consequently, both the mouse and human genetic data illustrate the importance of the system both developmentally and in adults.Renin is primarily expressed in renal juxtaglomerular (JG) cells in the wall of the af...

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Section: Discussionsupporting

confidence: 88%

The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

Zhoux

Davis

2006

Journal of Biological Chemistry

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“…1 A), reflecting the key role of AT 1 receptors in the development of hypertension in this model (MAP of 104 Ϯ 3 mmHg at Week 3). The modest (ϩ 6 Ϯ 3 mmHg; P ϭ 0.05) increase in blood pressure in these animals was likely mediated by expression of the minor AT 1 receptor isoform, AT 1B , which is unaffected by the AT 1A gene disruption (15).…”

Section: A Major Role For At1 Receptors In the Kidney In Ang Ii-depenmentioning

confidence: 88%

“…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). In the adrenal cortex, their activation stimulates the release of aldosterone (16) that in turn promotes sodium reabsorption in the mineralocorticoidresponsive segments of the distal nephron (17).…”

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.

624

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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“…Although knockout mice generated by gene-targeting in embryonic stem cells have provided important information on the function of the RAS, these studies are limited because the gene is eliminated from all tissues, and as a result, these animals exhibit premature death or severe organ dysfunction that precludes a detailed analysis of cardiovascular function (9,34,35). Similarly, although transgenic models containing the RAS genes have provided definitive evidence that overexpression of the system causes hypertension, the models have not been sufficient to address the organ-and cell-specific mechanisms involved (36;37).…”

Section: Discussionmentioning

confidence: 99%

Efficient Liver-specific Deletion of a Floxed Human Angiotensinogen Transgene by Adenoviral Delivery of Cre Recombinasein Vivo

Stec¹,

Davisson²,

Haskell

et al. 1999

Journal of Biological Chemistry

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Tissue-specific ablation of gene function is possible in vivo by the Cre-loxP recombinase system. We generated transgenic mice containing a human angiotensinogen gene flanked by loxP sites (hAGT flox ). To examine the physiologic consequences of tissue-specific loss of angiotensinogen gene function in vivo, we constructed an adenovirus expressing Cre recombinase. Studies were performed in several independent lines of hAGT flox mice before and after intravenous administration of either Adcre or Ad␤Gal as a control. Systemic administration of Adcre caused a significant decrease in circulating human angiotensinogen and markedly blunted the pressor response to administration of purified recombinant human renin. Southern blot analysis of genomic DNA from various organs revealed that the Cre-mediated deletion was liver-specific. Further analysis revealed the absence of full-length human angiotensinogen mRNA and protein in the liver but not the kidney of Adcre mice, consistent with the liver being the target for adenoviruses administered intravenously. These studies demonstrate that extra-hepatic sources of angiotensinogen do not contribute significantly to the circulating pool of angiotensinogen and provide proof-of-principle that the Cre-loxP system can be used effectively to examine the contribution of the systemic and tissue reninangiotensin system to normal and pathological regulation of blood pressure.

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Angiotensin II responses in AT1A receptor-deficient mice: a role for AT1B receptors in blood pressure regulation

Cited by 122 publications

References 0 publications

The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

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

Efficient Liver-specific Deletion of a Floxed Human Angiotensinogen Transgene by Adenoviral Delivery of Cre Recombinasein Vivo

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