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

Duke University, Durham, North Carolina, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2006; 103(47):17985-90. DOI: 10.1073/pnas.0605545103
Source: PubMed


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 (AT1) angiotensin receptor in essential hypertension, we developed an experimental model to separate AT1 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 AT1 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 AT1 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.

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    • "Sex differences in the RAS have been widely suggested to contribute to sexual dimorphisms in blood pressure and cardiovascular disease; the activity and expression level of numerous components of the RAS are modulated by both the sex chromosome complement of the animal and the gonadal hormone milieu. AT-1 receptors mediate the prohypertensive actions of Ang II, and renal AT-1 receptors in particular are critical to the development of Ang II hypertension in male mice (Crowley et al. 2006). In contrast, activation of the " nonclassical RAS pathway " (ACE2, Ang (1–7), angiotensin type 2 (AT-2), and Mas receptors opposes AT-1-mediated effects leading to vasodilation, improved blood flow, and enhanced pressure natriuresis (Sandberg and Ji 2003; Brewster and Perazella 2004; Sullivan et al. 2010a; Crowley and Coffman 2012; Chappell et al. 2014). "
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    ABSTRACT: We previously reported that male spontaneously hypertensive rats (SHRs) are more sensitive to chronic angiotensin (Ang) II-induced hypertension compared with female rats. This study was designed to test the hypothesis that anesthetized male SHRs are also more responsive to acute Ang II-induced increases in blood pressure and renal hemodynamic changes when compared with female SHRs. Baseline mean arterial pressure (MAP) was higher in male SHRs than in female SHRs (135 ± 2 vs. 124 ± 4 mmHg, P < 0.05). Acute intravenous infusion of Ang II (5 ng/kg/min) for 60 minutes significantly increased MAP to 148 ± 2 mmHg in male SHRs (P < 0.05) without a significant change in MAP in female SHRs. Baseline glomerular filtration rate (GFR) was also higher in male SHRs than in female SHRs (2.6 ± 0.3 vs. 1.3 ± 0.1 mL/min, P < 0.05). Ang II infusion for 60 min significantly decreased GFR in male SHRs (2.0 ± 0.2 mL/min; P < 0.05) without significant changes in urine flow rate, sodium, or chloride excretion. In contrast, Ang II infusion increased GFR in female SHRs (1.9 ± 0.2 mL/min; P < 0.05). The increase in GFR upon Ang II infusion in female SHRs was associated with increases in urine flow rate (4.3 ± 0.3 to 7.1 ± 0.9 μL/min), sodium excretion (0.16 ± 0.04 to 0.4 ± 0.1 μmol/min), and chloride excretion (0.7 ± 0.08 to 1.1 ± 0.1 μmol/min; for all P < 0.05). These findings support the hypothesis that there is sex difference in response to acute Ang II infusion in SHRs with females being less responsive to Ang II-induced elevations in blood pressure and decreases in GFR relative to male SHRs.
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    • "Measurements of sodium balance were carried out as previously described (Crowley et al., 2006). In brief, mice were placed into individual metabolic cages, and a gel diet containing nutrients, water and sodium (Nutra-Gel, Bio-serv, Frenchtown, NJ) was provided. "

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    • "It is a multifactorial disease that can be induced by genetic and environmental causes. While renal dysfunction is a primary cause of hypertension, vascular dysfunction associated with increased reactivity of arterial smooth muscle cells to the endogenous vasoconstrictor AngII [29] and impairment of endothelial cell-mediated vasodilation constitute major determinants of the disease [30] [31] [32]. Evidence collected over the last ten years indicates that AKAPs play a central role in integrating and transducing signaling pathways controlling vascular integrity, peripheral arteries vasoconstriction and hypertension . "
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    ABSTRACT: Heart and blood vessels ensure adequate perfusion of peripheral organs with blood and nutrients. Alteration of the homeostatic functions of the cardiovascular system can cause hypertension, atherosclerosis, and coronary artery disease leading to heart injury and failure. A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that are crucially involved in modulating the function of the cardiovascular system both under physiological and pathological conditions. AKAPs assemble multifunctional signaling complexes that ensure correct targeting of the cAMP-dependent protein kinase (PKA) as well as other signaling enzymes to precise subcellular compartments. This allows local regulation of specific effector proteins that control the function of vascular and cardiac cells. This review will focus on recent advances illustrating the role of AKAPs in cardiovascular pathophysiology. The accent will be mainly placed on the molecular events linked to the control of vascular integrity and blood pressure as well as on the cardiac remodeling process associated with heart failure.
    Full-text · Article · Nov 2015 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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