Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system

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

Research output: Contribution to journalArticle

244 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1092-1099
Number of pages8
JournalJournal of Clinical Investigation
Volume115
Issue number4
DOIs
StatePublished - Apr 2005

ASJC Scopus subject areas

  • Medicine(all)

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    Crowley, S. D., Gurley, S. B., Oliverio, M. I., Pazmino, A. K., Griffiths, R., Flannery, P. J., Spurney, R. F., Kim, H. S., Smithies, O., Le, T. H., & Coffman, T. M. (2005). Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. Journal of Clinical Investigation, 115(4), 1092-1099. https://doi.org/10.1172/JCI23378