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1.  Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system 
Journal of Clinical Investigation  2005;115(4):1092-1099.
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.
doi:10.1172/JCI200523378
PMCID: PMC1070417  PMID: 15841186
2.  Divergent functions of angiotensin II receptor isoforms in the brain 
Journal of Clinical Investigation  2000;106(1):103-106.
The renin-angiotensin system (RAS) plays a critical role in cardiovascular and fluid homeostasis. The major biologically active peptide of the RAS is angiotensin II, which acts through G protein–coupled receptors of two pharmacological classes, AT1 and AT2. AT1 receptors, expressed in brain and peripheral tissues, mediate most classically recognized actions of the RAS, including blood pressure homeostasis and regulation of drinking and water balance. In rodents, two highly homologous AT1 receptor isoforms, termed AT1A and AT1B receptors, are expressed at different levels in major forebrain cardiovascular and fluid regulatory centers, with AT1A expression generally exceeding AT1B expression, but the relative contributions of these receptor subtypes to central angiotensin II responses are not known. We used gene targeting in combination with a unique system for maintaining catheters in the cerebral ventricles of conscious mice to test whether there are differential roles for AT1A and AT1B receptors in responses elicited by angiotensin II in the brain. Here we show that the blood pressure increase elicited by centrally administered angiotensin II can be selectively ascribed to the AT1A receptor. However, the drinking response requires the presence of AT1B receptors. To our knowledge, this is the first demonstration of a primary and nonredundant physiological function for AT1B receptors.
PMCID: PMC314366  PMID: 10880053
3.  Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway 
Journal of Clinical Investigation  1999;104(12):1693-1701.
The renin-angiotensin system (RAS) is a key regulator of vascular tone and blood pressure. In addition, angiotensin II also has a number of cellular effects that may contribute to disease pathogenesis. Using Agtr1a–/– mice, which lack AT1A receptors for angiotensin II, we have identified a novel function of the RAS to modulate the immune system. We find that angiotensin II, acting through type 1 (AT1) receptors on immune cells, triggers the proliferation of splenic lymphocytes. These actions contribute to the vigor of cellular alloimmune responses. Within lymphoid organs, sufficient components of the RAS are present to activate AT1 receptors during an immune response, promoting cell growth. These actions require activation of calcineurin phosphatase. In an in vivo model of cardiac transplantation, the absence of AT1 signaling accentuates the immunosuppressive effects of the calcineurin inhibitor cyclosporine. We conclude that inhibition of AT1 receptor signaling should be useful as an anti-inflammatory and immunosuppressive therapy. Furthermore, the actions of the RAS to promote lymphocyte activation may contribute to inflammation that characterizes a number of diseases of the heart and the vascular system.
J. Clin. Invest. 104:1693–1701 (1999).
PMCID: PMC409880  PMID: 10606623

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