An intrinsic tissue-renin angiotensin system (RAS) is defined as a tissue- specific system with the potential for the local generation and action for Ang-II. We and others hypothesize that this local generation of Ang-II may provide a level of local control independent of the circulating (or endocrine) system. It has been shown that the kidney and brain both express each RAS gene mRNA and contains each RAS product. Therefore, the kidney and brain may have the capability of generating ANG-II from AGT released locally from renal proximal convoluted tubules (PCT) or astrocytes, respectively. Before the inception of this project, the concept that intrinsic tissue renin systems existed was highly controversial because it was not experimentally feasible to physiologically separate the effects of tissue RAS from the endocrine RAS. We have since provided the first convincing evidence in support of the blood pressure regulatory function of a tissue RAS in the kidney. This was accomplished with the use of a transgenic model in which angiotensinogen (AGT) was specifically targeted to renal PCT cells and studies demonstrating that transgenic mice expressing RAS components specifically within the kidney exhibited chronic hypertension without changes in circulating Ang-II. Importantly, we recently demonstrated that the cre-loxP recombinase system could be used as an effective tool to generate a tissue-specific knockout of RAS genes to experimentally dissect tissue RAS. We will examine the overall hypothesis that intrinsic tissue renin-angiotensin systems play an integral role in the regulation of blood pressure and may participate in the development or maintenance of hypertension. We will focus on the specific aims: 1) we will test the hypothesis that the intra-renal RAS plays a critical role in the regulation of blood pressure and renal function, and when specifically ablated via the cre-loxP recombinase system will reduce blood pressure in a model of Ang II-dependent hypertension, lower basal blood pressure in normotensive mice, and alter renal function and 2) we will explore the hypothesis that an intrinsic RAS in the brain, derived from locally synthesized AGT (and therefore Ang-II), plays an important role in the regulation of basal blood pressure, and when specifically ablated will lower blood pressure in a model of Ang-II-dependent hypertension by altering central effector mechanisms.
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