Atrap Deficiency Increases Arterial Blood Pressure and Plasma Volume

The angiotensin receptor-associated protein (Atrap) interacts with angiotensin II (AngII) type 1 (AT1) receptors and facilitates their internalization in vitro, but little is known about the function of Atrap in vivo. Here, we detected Atrap expression in several organs of wild-type mice; the highest expression was in the kidney where it localized to the proximal tubule, particularly the brush border. There was no Atrap expression in the renal vasculature or juxtaglomerular cells. We generated Atrap-deficient (Atrap−/−) mice, which were viable and seemed grossly normal. Mean systolic BP was significantly higher in Atrap−/− mice compared with wild-type mice. Dose-response relationships of arterial BP after acute AngII infusion were similar in both genotypes. Plasma volume was significantly higher and plasma renin concentration was markedly lower in Atrap−/− mice compared with wild-type mice. ¹²⁵I-AngII binding showed enhanced surface expression of AT1 receptors in the renal cortex of Atrap−/− mice, accompanied by increased carboanhydrase-sensitive proximal tubular function. In summary, Atrap−/− mice have increased arterial pressure and plasma volume. Atrap seems to modulate volume status by acting as a negative regulator of AT1 receptors in the renal tubules.Angiotensin II (AngII) is the primary end point of the renin-angiotensin (RAS) cascade. AngII exerts multiple functions, including mediation of vasoconstriction, stimulation of aldosterone release, and promotion of renal salt/water reabsorption. These classical effects of AngII, which eventually all result in a rise of arterial blood pressure (BP), are thought to be primarily mediated by AngII type 1 (AT1) receptors. Because changes in the activity of the systemic RAS cascade similarly affect all different accessible target tissues, it is reasonable to assume that strategies that allow for local and temporal modification of the sensitivity of AT1 receptors have evolved. In this context, modulation of AT1 receptor expression, receptor desensitization, and internalization all have been described to modify locally the AT1-related effects of AngII.^1–8 In addition, a growing number of proteins seem to bind to the AT1 receptor and either enhance or suppress AT1 receptor function.^9–13Of the known proteins that can interact with AT1 receptors, the function of the angiotensin receptor–associated protein (Atrap) is the best characterized.^10,14 Atrap is a 19-kD protein with three potential transmembrane domains, and it binds to the C-terminal intracellular portion of the AT1 receptor.¹⁵ Atrap catalyzes the internalization of the AT1 receptor in cultured vascular smooth muscle cells.^14,16 Also, Atrap inhibits AngII-mediated intracellular signaling in vitro.¹⁷ Overall, the data suggest an inhibitory effect of Atrap on AT1 receptor function in vitro.Regarding the in vivo function of Atrap, a recently generated transgenic mouse line with overexpression of Atrap in the heart, aorta, and femoral artery showed reduced inflammatory vascular remodeling and reduced heart hypertrophy as compared with transgene-negative controls.¹⁸ The authors concluded that Atrap attenuates AT1-mediated signaling under pathophysiologic conditions.¹⁸To assess the in vivo function of Atrap, we generated Atrap-deficient (Atrap−/−) mice. Vascular responsiveness to AngII was virtually unaltered in Atrap−/− mice compared with wild-type mice; however, loss of Atrap resulted in increased plasma volume and elevated arterial BP. Renal cortical AngII binding and acetazolamide-sensitive tubular function were enhanced in Atrap−/− mice compared with wild-type controls. We propose that Atrap is a negative modulator of renal AngII signaling and that loss of Atrap results in enhanced renal reabsorptive function, leading to volume expansion and hypertension.