AT1A angiotensin receptors in the renal proximal tubule regulate blood pressure - PubMed (original) (raw)

AT1A angiotensin receptors in the renal proximal tubule regulate blood pressure

Susan B Gurley et al. Cell Metab. 2011.

Abstract

Hypertension affects more than 1.5 billion people worldwide but the precise cause of elevated blood pressure (BP) cannot be determined in most affected individuals. Nonetheless, blockade of the renin-angiotensin system (RAS) lowers BP in the majority of patients with hypertension. Despite its apparent role in hypertension pathogenesis, the key cellular targets of the RAS that control BP have not been clearly identified. Here we demonstrate that RAS actions in the epithelium of the proximal tubule have a critical and nonredundant role in determining the level of BP. Abrogation of AT(1) angiotensin receptor signaling in the proximal tubule alone is sufficient to lower BP, despite intact vascular responses. Elimination of this pathway reduces proximal fluid reabsorption and alters expression of key sodium transporters, modifying pressure-natriuresis and providing substantial protection against hypertension. Thus, effectively targeting epithelial functions of the proximal tubule of the kidney should be a useful therapeutic strategy in hypertension.

Copyright © 2011 Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. Baseline studies in PTKO mice

(A) 12-hour mean systolic BPs during the day (d) and at night (n) on a control diet. Systolic BPs were significantly lower in PTKO mice compared to controls (*p=0.03). (B) BPs increased significantly (†p<0.01) and to a similar extent in PTKO and controls during high salt (6% NaCl) feeding and returned to baseline values on low salt (<0.02% NaCl). BPs were significantly lower in the PTKOs throughout the experiment (*p<0.044). (C) The maximal increases in mean arterial pressure (MAP) compared to baseline in response to bolus infusions of angiotensin II (1 and 10 μg/kg) or epinephrine (10 μg/kg) were identical between PTKOs and controls. (D) Rates of fluid reabsorption by the renal PT measured in vivo using standard free flow micropuncture were significantly reduced in the PTKO mice compared to controls as an absolute rate (p=0.00011) or (F) when adjusted for single-nephron glomerular filtration rate (p=0.0007). Error bars represent SEM.

Figure 2

Figure 2. AT1A receptors in the proximal tubule promote hypertension

(A) With infusion of ang II (1000ng/kg/min), BPs increased significantly in both control and PTKO mice but the hypertensive response to angiotensin II was significantly attenuated in the PTKOs (**p<0.001). (B) The mean increase in BP during the angiotensin II infusion was significantly less in the PTKOs (23±3 mm Hg) compared to controls (black bars; 38±5 mm Hg, *p=0.0005). (C) Cumulative sodium balance was significantly lower in the PTKOs (n=8) than controls (n=7, *p=0.046) during the first 3 days of ang II infusion. Error bars represent SEM.

Figure 3

Figure 3. Abundance of Sodium Transporters in Control and PTKO mice

Protein levels of key transporters in kidneys of PTKO and control mice including NHE3 (A, B), NaPi2 (C,D), and NKCC2 (E, F) were measured by western blot. Numbers below the blots indicate the mean ± S.E.M of the sample density normalized to the control baseline set (arbitrarily defined as 1.0). The densitometry data are in bar graphs (B, D, and F) where * indicates p<0.05.

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