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.
Natriuretic peptides, produced in the heart, bind to the natriuretic peptide receptor A (NPRA) and cause vasodilation and natriuresis important in the regulation of blood pressure. We here report that mice lacking a functional Npr1 gene coding for NPRA have elevated blood pressures and hearts exhibiting marked hypertrophy with interstitial fibrosis resembling that seen in human hypertensive heart disease. Echocardiographic evaluation of the mice demonstrated a compensated state of systemic hypertension in which cardiac hypertrophy and dilatation are evident but with no reduction in ventricular performance. Nevertheless, sudden death, with morphologic evidence indicative in some animals of congestive heart failure and in others of aortic dissection, occurred in all 15 male mice lacking Npr1 before 6 months of age, and in one of 16 females in our study. Thus complete absence of NPRA causes hypertension in mice and leads to cardiac hypertrophy and, particularly in males, lethal vascular events similar to those seen in untreated human hypertensive patients.
The classically recognized functions of the renin-angiotensin system are mediated by type 1 (AT 1 ) angiotensin receptors. Whereas man possesses a single AT 1 receptor, there are two AT 1 receptor isoforms in rodents (AT 1A and AT 1B ) that are products of separate genes (Agtr1a and Agtr1b). We have generated mice lacking AT 1B (Agtr1b ؊͞؊) and both AT 1A and AT 1B receptors (Agtr1a ؊͞؊Agtr1b ؊͞؊). Agtr1b ؊͞؊ mice are healthy, without an abnormal phenotype. In contrast, Agtr1a ؊͞؊Agtr1b ؊͞؊ mice have diminished growth, vascular thickening within the kidney, and atrophy of the inner renal medulla. This phenotype is virtually identical to that seen in angiotensinogen-deficient (Agt؊͞؊) and angiotensin-converting enzyme-deficient (Ace ؊͞؊) mice that are unable to synthesize angiotensin II. Agtr1a ؊͞؊Agtr1b ؊͞؊ mice have no systemic pressor response to infusions of angiotensin II, but they respond normally to another vasoconstrictor, epinephrine. Blood pressure is reduced substantially in the Agtr1a ؊͞؊ Agtr1b ؊͞؊ mice and following administration of an angiotensin converting enzyme inhibitor, their blood pressure increases paradoxically. We suggest that this is a result of interruption of AT 2 -receptor signaling. In summary, our studies suggest that both AT 1 receptors promote somatic growth and maintenance of normal kidney structure. The absence of either of the AT 1 receptor isoforms alone can be compensated in varying degrees by the other isoform. These studies reaffirm and extend the importance of AT 1 receptors to mediate physiological functions of the renin-angiotensin system.The renin-angiotensin system (RAS) regulates blood pressure and body fluid balance and plays a role in growth and development (1-3). The biological functions of the RAS and its major effector peptide, angiotensin II, are mediated by specific receptors. Two angiotensin receptor subtypes, type 1 angiotensin receptor (AT 1 ) and AT 2 , can be distinguished pharmacologically. The classically recognized actions of the RAS are mediated by AT 1 receptors (1, 2). Whereas man possesses a single AT 1 receptor, rodents possess two AT 1 receptor isoforms, designated AT 1A and AT 1B . These receptors are the products of distinct but highly homologous genes (Agtr1a and Agtr1b) located on separate chromosomes (3, 4). Expression of the AT 1A receptor subtype predominates in nearly all tissues except the anterior pituitary gland and the adrenal cortex, where AT 1B receptors are more highly expressed (5-9). Because pharmacological AT 1 receptor antagonists block both AT 1A and AT 1B receptors, it has been difficult to separate their distinct functions (2).Experiments using gene targeting have provided insight into the roles of RAS genes in regulating blood pressure, body fluid homeostasis, and development. For example, mice that are unable to generate angiotensin II because of targeted mutations in the angiotensinogen (Agt Ϫ͞Ϫ) or angiotensinconverting enzyme (Ace Ϫ͞Ϫ) genes have virtually identical phenotypes characterized by reduced survival, l...
Most of the classic functions of the renin-angiotensin system are mediated by type 1 (AT1) angiotensin receptors, of which two subtypes, AT1A and AT1B, have been identified. However, distinct functions for these two AT1 receptors have been difficult to separate. We examined the pressor effects of angiotensin II in Agtr1A -/- mice, which lack AT1A receptors. In enalapril-pretreated Agtr1A -/- mice, angiotensin II caused significant and dose-proportional increases in mean arterial pressure. This pressor response was not blocked by pretreatment with sympatholytic agents but was completely inhibited by the AT1-receptor antagonists, losartan and candesartan, suggesting that it is directly mediated by AT1B receptors. Chronic treatment of Agtr1A -/- mice with losartan reduced systolic blood pressure from 80 +/- 5 to 72 +/- 4 mmHg (P < 0.04), suggesting a role for AT1B receptors in chronic blood pressure regulation. These studies provide the first demonstration of in vivo pressor effects mediated by AT1B receptors and demonstrate that, when AT1A receptors are absent, the AT1B receptor contributes to the regulation of resting blood pressure.
cyte responses exacerbate angiotensin II-dependent hypertension. Am J Physiol Regul Integr Comp Physiol 298: R1089-R1097, 2010. First published February 10, 2010 doi:10.1152/ajpregu.00373.2009.-Activation of the immune system by ANG II contributes to the pathogenesis of hypertension, and pharmacological suppression of lymphocyte responses can ameliorate hypertensive end-organ damage. Therefore, to examine the mechanisms through which lymphocytes mediate blood pressure elevation, we studied ANG II-dependent hypertension in scid mice lacking lymphocyte responses and wild-type controls. Scid mice had a blunted hypertensive response to chronic ANG II infusion and accordingly developed less cardiac hypertrophy. Moreover, lymphocyte deficiency led to significant reductions in heart and kidney injury following 4 wk of angiotensin. The muted hypertensive response in the scid mice was associated with increased sodium excretion, urine volumes, and weight loss beginning on day 5 of angiotensin infusion. To explore the mechanisms underlying alterations in blood pressure and renal sodium handling, we measured gene expression for vasoactive mediators in the kidney after 4 wk of ANG II administration. Scid mice and controls had similar renal expression for interferon-␥, interleukin-1, and interleukin-6. By contrast, lymphocyte deficiency (i.e., scid mice) during ANG II infusion led to upregulation of tumor necrosis factor-␣, endothelial nitric oxide synthase (eNOS), and cyclooxygenase-2 (COX-2) in the kidney. In turn, this enhanced eNOS and COX-2 expression in the scid kidneys was associated with exaggerated renal generation of nitric oxide, prostaglandin E2, and prostacyclin, all of which promote natriuresis. Thus, the absence of lymphocyte activity protects from hypertension by allowing blood pressure-induced sodium excretion, possibly via stimulation of eNOSand COX-2-dependent pathways.inflammation; kidney diseases; T lymphocytes THE RENIN-ANGIOTENSIN SYSTEM (RAS) is a critical regulator of blood pressure and fluid homeostasis. The principal effector molecule of this system, angiotensin II (ANG II) raises blood pressure primarily through activation of type 1 angiotensin (AT 1 ) receptors (11). The important role of AT 1 receptors in the pathogenesis of hypertension is illustrated by clinical trials that show the impressive efficacy of AT 1 receptor blockers (ARBs) in ameliorating hypertension and its complications, including chronic kidney disease (CKD) and cardiac hypertrophy (3, 13, 37).In these trials, RAS inhibition appears to protect from end-organ damage to a greater degree than can be explained solely by blood pressure reduction (3, 63). Blockade of proinflammatory cellular effects of ANG II represents one blood pressure-independent mechanism through which ARB therapy could protect against target organ injury. For example, ANG II stimulates NF-B activation and interferon-␥ expression in the kidney, and immunosuppression can reverse these effects (8,45,46). Moreover, ANG II can drive lymphocyte proliferation (48), a...
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