CELLULAR MECHANISMS FOR ANGIOTENSIN RESPONSES IN BRAIN

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The central renin-angiotensin system (RAS) participates in the control of arterial pressure. Angiotensin (Ang) II receptors are present on neurons, astrocytes and vascular elements and likely cooperate in this regulation. During the current funding period, we showed that 1) region-specific astrocytes differentially contain high affinity Ang II receptors and a high affinity internalization site; 2) these receptors are differentially coupled to phospholipase C and the release of prostacyclin; 3) Ang II differentially regulates expression of the mRNA for angiotensinogen (Aogen) in region-specific astrocytes, which may be regulated by a nuclear Ang II receptor that responds to the internalized Ang II receptors coupled to phospholipase C are desensitized in astrocytes isolated from hypertensive (mRen-2)27 rats. In the current application, these studies will be expanded to identify the role of the glial RAS in the pathobiology of hypertension, using this hypertensive rat model in which the central RAS is overexpressed. The (mRen-2) 27 transgenic (TG) rat was developed by insertion of the mouse submandibular renin gene into the rat genome. The transgene and elevated levels of Ang II are present in TG rat brain as compared to normotensive controls. While Ang II receptors in the medulla and hypothalamus are similar in the TG rat as compared to controls, Ang II-induced vasopressin release from the hypothalamus is attenuated in agreement with the reduced phospholipase C activity that we observe in cultured astrocytes. We hypothesize that overexpression of th renin transgene in TG rat brain elevates the levels of Ang II and upregulates the production of Aogen by astrocytes. We further hypothesize that AT1 receptors on astrocytes isolated from TG rat brain are desensitized, resulting in reduced secretion of plasminogen activator inhibitor-1 (PAI- 1) and elevated production of active renin from prorenin. This results in overproduction of Aogen and active renin, producing elevated levels of Ang II, increased sympathetic outflow and an increase in blood pressure. In this application, we propose to demonstrate that Ang II levels are elevated in cultured astrocytes isolated from TG rat brain due to over- expression of renin. We will determine whether AT1 receptors are desensitized by the elevated levels of Ang II, leading to decreased production of PAI-1. Furthermore, we will determine whether Aogen mRNA expression is un-regulated by the elevated levels of Ang II in TG rat astrocytes and whether this occurs through activation of a nuclear Ang II receptor. Finally, we will demonstrate that desensitization of the plasma membrane AT1 receptor and overexpression of Aogen in TG rat astrocytes can be prevented by reducing endogenous Ang II levels or by blocking AT1 receptors. These studies will extend our understanding of the role of the central RAS in blood pressure regulation and provide insight into the pathology of forms of essential human hypertension where endogenous levels of Ang II are elevated.