The absence of intrarenal ACE protects against hypertension
Romer A. Gonzalez-Villalobos, … , Kenneth E. Bernstein, Alicia A. McDonough
Romer A. Gonzalez-Villalobos, … , Kenneth E. Bernstein, Alicia A. McDonough
Published April 24, 2013
Citation Information: J Clin Invest. 2013;123(5):2011-2023. https://doi.org/10.1172/JCI65460.
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Research Article

The absence of intrarenal ACE protects against hypertension

Abstract

Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension. Here, we show that the absence of kidney ACE substantially blunts the hypertension induced by Ang II infusion (a model of high serum Ang II) or by nitric oxide synthesis inhibition (a model of low serum Ang II). Moreover, the renal responses to high serum Ang II observed in wild-type mice, including intrarenal Ang II accumulation, sodium and water retention, and activation of ion transporters in the loop of Henle (NKCC2) and distal nephron (NCC, ENaC, and pendrin) as well as the transporter activating kinases SPAK and OSR1, were effectively prevented in mice that lack kidney ACE. These findings demonstrate that ACE metabolism plays a fundamental role in the responses of the kidney to hypertensive stimuli. In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension.

Authors

Romer A. Gonzalez-Villalobos, Tea Janjoulia, Nicholas K. Fletcher, Jorge F. Giani, Mien T.X. Nguyen, Anne D. Riquier-Brison, Dale M. Seth, Sebastien Fuchs, Dominique Eladari, Nicolas Picard, Sebastian Bachmann, Eric Delpire, Janos Peti-Peterdi, L. Gabriel Navar, Kenneth E. Bernstein, Alicia A. McDonough

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Figure 1

The absence of kidney ACE blunts the hypertensive response to Ang II infusion or l-NAME.

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The absence of kidney ACE blunts the hypertensive response to Ang II inf...
(A) Systolic blood pressure (SBP) of wild-type, ACE 10/10, and ACE 3/3 mice after 2 weeks of Ang II infusion (400 ng/kg/min via minipump). Blood pressure was measured by tail-cuff plethysmography. n = 6–22 per group. The corresponding background strain is indicated. (B) Systolic blood pressure of wild-type, ACE 10/10, and ACE 3/3 mice after 2 weeks of l-NAME treatment (5 mg/10 ml in the drinking water). n = 6–9 per group. (C) MAP of wild-type and ACE 10/10 mice during chronic Ang II infusion. MAP was recorded by telemetry. n = 7–8 per group. Uninfused, sham-operated mice; Basal, mice not receiving l-NAME in the drinking water. *P < 0.05, **P < 0.01, ****P < 0.0001. Values represent individual mice and mean ± SEM.