Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system.
Angiotensin II, acting through type 1 angiotensin (AT(1)) 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 AT(1) 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 AT(1A) receptor-deficient mice to demonstrate distinct and virtually equivalent contributions of AT(1) 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 AT(1A) receptors cannot be explained by altered aldosterone generation, which suggests that AT(1) 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 AT(1) receptor-mediated short-loop feedback in the kidney is not sufficient to explain the marked stimulation of renin production induced by global AT(1) 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 AT(1) receptors both within and outside the kidney.
Crowley
Steven D
SD
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina 27705, USA.
Gurley
Susan B
SB
Oliverio
Michael I
MI
Pazmino
A Kathy
AK
Griffiths
Robert
R
Flannery
Patrick J
PJ
Spurney
Robert F
RF
Kim
Hyung-Suk
HS
Smithies
Oliver
O
Le
Thu H
TH
Coffman
Thomas M
TM
D000315:Adrenalectomy; D000450:Aldosterone / Q000652:urine; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D001795:Blood Pressure Determination; D004032:Diet; D006706:Homeostasis; D007668:Kidney / Q000502:physiology*; D016030:Kidney Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D012492:Salts / Q000008:administration & dosage / Q000378:metabolism
D044140:Receptor, Angiotensin, Type 1; D012492:Salts; D000804:Angiotensin II; D000450:Aldosterone; D012083:Renin; D009638:Norepinephrine