title: AT1A angiotensin receptors in the renal proximal tubule regulate blood pressure.
abstract: Hypertension affects more than 1.5 billion people worldwide but the precise cause of elevated blood pressure (BP) cannot be determined in most affected individuals. Nonetheless, blockade of the renin-angiotensin system (RAS) lowers BP in the majority of patients with hypertension. Despite its apparent role in hypertension pathogenesis, the key cellular targets of the RAS that control BP have not been clearly identified. Here we demonstrate that RAS actions in the epithelium of the proximal tubule have a critical and nonredundant role in determining the level of BP. Abrogation of AT(1) angiotensin receptor signaling in the proximal tubule alone is sufficient to lower BP, despite intact vascular responses. Elimination of this pathway reduces proximal fluid reabsorption and alters expression of key sodium transporters, modifying pressure-natriuresis and providing substantial protection against hypertension. Thus, effectively targeting epithelial functions of the proximal tubule of the kidney should be a useful therapeutic strategy in hypertension.
authors: Division of Nephrology, Department of Medicine, Duke University and Durham, VA Medical Centers, Durham, NC 27710, USA.
authors: Susan B
authors: SB
authors: Gurley
authors: Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA 90089, USA.
authors: Anne D M
authors: ADM
authors: Riquier-Brison
authors: National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Jurgen
authors: J
authors: Schnermann
authors: Division of Nephrology, Department of Medicine, Duke University and Durham, VA Medical Centers, Durham, NC 27710, USA.
authors: Matthew A
authors: MA
authors: Sparks
authors: Department of Physiology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors: Andrew M
authors: AM
authors: Allen
authors: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors: Volker H
authors: VH
authors: Haase
authors: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: John N
authors: JN
authors: Snouwaert
authors: Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors: Thu H
authors: TH
authors: Le
authors: Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA 90089, USA.
authors: Alicia A
authors: AA
authors: McDonough
authors: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Beverley H
authors: BH
authors: Koller
authors: Division of Nephrology, Department of Medicine, Duke University and Durham, VA Medical Centers, Durham, NC 27710, USA; Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Graduate Medical School, Singapore 169857. Electronic address: tcoffman@duke.edu.
authors: Thomas M
authors: TM
authors: Coffman
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D006973:Hypertension / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1
chemical_list: D044140:Receptor, Angiotensin, Type 1; C578715:Slc12a1 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D012964:Sodium