J Clin Invest. 2007 April 2; 117(4): 873–876.
doi: 10.1172/JCI31856
doi: 10.1172/JCI31856
Kelly K. Parsons and Thomas M. Coffman
Division of Nephrology, Department of Medicine, Duke University School of Medicine, and Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.
Division of Nephrology, Department of Medicine, Duke University School of Medicine, and Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.
Components of the renin-angiotensin system (RAS) are expressed in a number of areas in the brain involved in cardiovascular control. However, it has been difficult to link RAS actions in circumscribed brain regions to specific physiological functions. In a study appearing in this issue of the JCI, Sakai and associates use a combination of sophisticated transgenic techniques and stereotaxic microinjection of recombinant viral vectors to demonstrate a pivotal role in the regulation of thirst and salt appetite of angiotensin II generated in the subfornical organ in the brain.The capacity of the CNS to respond directly to angiotensin II was demonstrated in experiments more than 2 decades ago, wherein angiotensin II was injected into cerebral ventricles or specific brain nuclei and it subsequently elicited potent cardiovascular and dipsogenic (thirst-provoking) responses (6, 7). Expression of virtually all of the components of the RAS has since been verified in various regions and cell lineages in the brain. Based on these findings, it was suggested that angiotensin II generated locally in the brain might function as a putative neurotransmitter in neurons involved in cardiovascular regulation (8). Within the brain, the subfornical organ (SFO) is a major site of RAS activity that has also been implicated as an important cardiovascular control center. Injection of angiotensin II into the SFO activates its neurons and elicits potent systemic vasoconstriction . While angiotensinogen and angiotensin receptors are highly expressed within the SFO (10–14), it lies outside of the blood-brain barrier and therefore is also potentially subject to modulation by components of the RAS in the circulation.
Many of the general features of the brain RAS have been apparent for some time. Until recently, however, it has been difficult to develop a precise understanding of its contributions to physiological homeostasis in the intact organism. This was due to a number of experimental barriers, including gaps in expression patterns of RAS components between regions and difficulties in precisely manipulating the brain RAS in vivo. The development of techniques for transgenesis and gene targeting advanced the field, but the lack of promoters to drive expression in specific brain regions remains a significant limitation. In the current study by Sakai and associates (4), along with another recent publication by the same group (5), transgenic mouse lines expressing RAS genes have been utilized in combination with microinjection of recombinant viral vectors to establish a critical contribution of angiotensin II generation within the SFO to the control of thirst and systemic vasopressor responses
Many of the general features of the brain RAS have been apparent for some time. Until recently, however, it has been difficult to develop a precise understanding of its contributions to physiological homeostasis in the intact organism. This was due to a number of experimental barriers, including gaps in expression patterns of RAS components between regions and difficulties in precisely manipulating the brain RAS in vivo. The development of techniques for transgenesis and gene targeting advanced the field, but the lack of promoters to drive expression in specific brain regions remains a significant limitation. In the current study by Sakai and associates (4), along with another recent publication by the same group (5), transgenic mouse lines expressing RAS genes have been utilized in combination with microinjection of recombinant viral vectors to establish a critical contribution of angiotensin II generation within the SFO to the control of thirst and systemic vasopressor responses
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