title: Impact of Angiotensin Type 1A Receptors in Principal Cells of the Collecting Duct on Blood Pressure and Hypertension.
abstract: The main actions of the renin-angiotensin system to control blood pressure (BP) are mediated by the angiotensin type 1 receptors (AT1Rs). The major murine AT1R isoform, AT1AR, is expressed throughout the nephron, including the collecting duct in both principal and intercalated cells. Principal cells play the major role in sodium and water reabsorption. Although aldosterone is considered to be the dominant regulator of sodium reabsorption by principal cells, recent studies suggest a role for direct actions of AT1R. To specifically examine the contributions of AT1AR in principal cells to BP regulation and the development of hypertension in vivo, we generated inbred 129/SvEv mice with deletion of AT1AR from principal cells (PCKO). At baseline, we found that BPs measured by radiotelemetry were similar between PCKOs and controls. During 1-week of low-salt diet (<0.02% NaCl), BPs fell significantly (P<0.05) and to a similar extent in both groups. On a high-salt (6% NaCl) diet, BP increased but was not different between groups. During the initial phase of angiotensin II-dependent hypertension, there was a modest but significant attenuation of hypertension in PCKOs (163±6 mm Hg) compared with controls (178±2 mm Hg; P<0.05) that was associated with enhanced natriuresis and decreased alpha epithelial sodium channel activation in the medulla of PCKOs. However, from day 9 onward, BPs were indistinguishable between groups. Although effects of AT1AR on baseline BP and adaptation to changes in dietary salt are negligible, our studies suggest that direct actions of AT1AR contribute to the initiation of hypertension and epithelial sodium channel activation.
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University, and Durham VA Medical Centers, NC (D.C., M.A.S., R.G., M.H., S.B.G., T.M.C.); Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany (J.S.); School of Medicine, University of Utah Health Sciences Center, Salt Lake City (D.K.); and Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Graduate Medical School, Singapore, Singapore (T.M.C.).
authors.forename: Daian
authors.initials: D
authors.lastname: Chen
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University, and Durham VA Medical Centers, NC (D.C., M.A.S., R.G., M.H., S.B.G., T.M.C.); Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany (J.S.); School of Medicine, University of Utah Health Sciences Center, Salt Lake City (D.K.); and Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Graduate Medical School, Singapore, Singapore (T.M.C.).
authors.forename: Johannes
authors.initials: J
authors.lastname: Stegbauer
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University, and Durham VA Medical Centers, NC (D.C., M.A.S., R.G., M.H., S.B.G., T.M.C.); Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany (J.S.); School of Medicine, University of Utah Health Sciences Center, Salt Lake City (D.K.); and Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Graduate Medical School, Singapore, Singapore (T.M.C.).
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sparks
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University, and Durham VA Medical Centers, NC (D.C., M.A.S., R.G., M.H., S.B.G., T.M.C.); Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany (J.S.); School of Medicine, University of Utah Health Sciences Center, Salt Lake City (D.K.); and Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Graduate Medical School, Singapore, Singapore (T.M.C.).
authors.forename: Donald
authors.initials: D
authors.lastname: Kohan
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University, and Durham VA Medical Centers, NC (D.C., M.A.S., R.G., M.H., S.B.G., T.M.C.); Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany (J.S.); School of Medicine, University of Utah Health Sciences Center, Salt Lake City (D.K.); and Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Graduate Medical School, Singapore, Singapore (T.M.C.).
authors.forename: Robert
authors.initials: R
authors.lastname: Griffiths
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University, and Durham VA Medical Centers, NC (D.C., M.A.S., R.G., M.H., S.B.G., T.M.C.); Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany (J.S.); School of Medicine, University of Utah Health Sciences Center, Salt Lake City (D.K.); and Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Graduate Medical School, Singapore, Singapore (T.M.C.).
authors.forename: Marcela
authors.initials: M
authors.lastname: Herrera
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University, and Durham VA Medical Centers, NC (D.C., M.A.S., R.G., M.H., S.B.G., T.M.C.); Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany (J.S.); School of Medicine, University of Utah Health Sciences Center, Salt Lake City (D.K.); and Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Graduate Medical School, Singapore, Singapore (T.M.C.).
authors.forename: Susan B
authors.initials: SB
authors.lastname: Gurley
authors.affiliation: From the Division of Nephrology, Department of Medicine, Duke University, and Durham VA Medical Centers, NC (D.C., M.A.S., R.G., M.H., S.B.G., T.M.C.); Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany (J.S.); School of Medicine, University of Utah Health Sciences Center, Salt Lake City (D.K.); and Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Graduate Medical School, Singapore, Singapore (T.M.C.). tcoffman@duke.edu.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D011897:Random Allocation; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012016:Reference Values; D012084:Renin-Angiotensin System / Q000502:physiology*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II
keywords: angiotensin AT1A receptor; angiotensin II; blood pressure; epithelial sodium channel blockers; hypertension