Angiotensin II, acting through type 1 angiotensin (AT1) receptors, has potent effects that alter renal excretory mechanisms. Control of sodium excretion by the kidney has been suggested to be the critical mechanism for blood pressure regulation by the renin-angiotensin system (RAS). However, since AT1 receptors are ubiquitously expressed, precisely dissecting their physiological actions in individual tissue compartments including the kidney with conventional pharmacological or gene targeting experiments has been difficult. Here, we used a cross-transplantation strategy and AT1A receptor–deficient mice to demonstrate distinct and virtually equivalent contributions of AT1 receptor actions in the kidney and in extrarenal tissues to determining the level of blood pressure. We demonstrate that regulation of blood pressure by extrarenal AT1A receptors cannot be explained by altered aldosterone generation, which suggests that AT1 receptor actions in systemic tissues such as the vascular and/or the central nervous systems make nonredundant contributions to blood pressure regulation. We also show that interruption of the AT1 receptor–mediated short-loop feedback in the kidney is not sufficient to explain the marked stimulation of renin production induced by global AT1 receptor deficiency or by receptor blockade. Instead, the renin response seems to be primarily determined by renal baroreceptor mechanisms triggered by reduced blood pressure. Thus, the regulation of blood pressure by the RAS is mediated by AT1 receptors both within and outside the kidney.
Steven D. Crowley, Susan B. Gurley, Michael I. Oliverio, A. Kathy Pazmino, Robert Griffiths, Patrick J. Flannery, Robert F. Spurney, Hyung-Suk Kim, Oliver Smithies, Thu H. Le, Thomas M. Coffman
Title and authors | Publication | Year |
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Gain-of-function mutant of Angiotensin II AT1A Receptor causes Hypertension and Cardiovascular Fibrosis in Mice
Sandrine BILLET, Sabine BARDIN, Sonia VERP, Véronique BAUDRIE, Annie MICHAUD, Sophie CONCHON, Martine MUFFAT-JOLY, Brigitte ESCOUBET, Evelyne SOUIL, Ghislaine HAMARD, Kenneth E. BERNSTEIN, Jean Marie GASC, Jean-Luc ELGHOZI, Pierre CORVOL & Eric CLAUSER |
Journal of Clinical Investigation | 2007 |
Anti-hypertensive Effects of Selective Prostaglandin E2 EP1 Receptor Targeting
Youfei Guan, Yahua Zhang, Zhonghua Qi, Guangrui Yang, Dou Dou=, Yuansheng Gao, Jing Wu, Lihong Chen, Xiaoyan Zhang, Linda S. Davis, Mingfeng Wei, Xuefeng Fan, Monica Carmosino, Chuanming Hao, John D. Imig, Richard M. Breyer, Matthew D. Breyer |
Journal of Clinical Investigation | 2007 |
In hypertension, the kidney rules
SD Crowley, TM Coffman |
Current Hypertension Reports | 2007 |
Hypertension and albuminuria in chronic kidney disease mapped to a mouse chromosome 11 locus
HR Salzler, R Griffiths, P Ruiz, L Chi, C Frey, DA Marchuk, HA Rockman, TH Le |
Kidney International | 2007 |
Development of an AT2-deficient proximal tubule cell line for transport studies
PG Woost, RJ Kolb, CH Chang, M Finesilver, T Inagami, U Hopfer |
In vitro cellular & developmental biology. Animal | 2007 |
Renovascular hypertension in 2007: where are we now?
Textor SC |
Current Cardiology Reports | 2007 |