title: Role of AT₁ receptor-mediated salt retention in angiotensin II-dependent hypertension.
abstract: Activation of type 1 angiotensin II (AT(1)) receptors in the kidney promotes blood pressure elevation and target organ damage, but whether renal AT(1) receptors influence the level of hypertension by stimulating sodium retention or by raising systemic vascular resistance has not been established. In the current studies, we used a kidney cross-transplantation strategy to determine whether increased sodium reabsorption by AT(1) receptors in the kidney mediates the chronic hypertensive response to angiotensin II. We found this to be true. In addition, we also identified a second, nontrivial component of blood pressure elevation induced by activation of renal AT(1) receptors that is sodium-independent. As the kidney has the capacity to limit the transmission of elevated systemic blood pressure into the renal microcirculation, prior studies struggled to clearly discriminate the relative contributions of blood pressure elevation vs. activation of AT(1) receptors to hypertensive kidney injury. In our model, we found that rapid surges in blood pressure, which may overcome the kidney's capacity to prevent perturbations in renal hemodynamics, correlate closely with kidney damage in hypertension. Moreover, maximal kidney injury in hypertension may require activation of a pool of nonrenal, systemic AT(1) receptors. These studies provide insight into precise mechanisms through which AT(1) receptor blockade influences the progression of hypertensive kidney disease.
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, North Carolina, USA. crowl004@mc.duke.edu
authors.forename: Steven D
authors.initials: SD
authors.lastname: Crowley
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.forename: Maria
authors.initials: M
authors.lastname: Herrera
authors.forename: Robert
authors.initials: R
authors.lastname: Griffiths
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
mesh_terms: D000419:Albuminuria / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000517:prevention & control; D004039:Diet, Sodium-Restricted; D018450:Disease Progression; D006977:Hypertension, Renal / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000473:pathology / Q000502:physiology; D016030:Kidney Transplantation / Q000502:physiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D012492:Salts / Q000378:metabolism*
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D012492:Salts; D000804:Angiotensin II