The long-term goal of this project is to delineate the precise mechanisms that control intrarenal angiotensin II generation and its impact on kidney function. It is known that Angiotensin (Ang II)-dependent hypertension is characterized by an increase in intrarenal Ang II levels that are associated with functional and morphological derangements in the kidney. Such augmentation involves an enhanced intrarenal Ang II synthesis by the local renin-angiotensin system (RAS) but, the exact contribution of intrarenal Ang II generation to the augmentation of Ang II in the kidney and the disturbances observed in this organ during Ang ll-dependent hypertension remains to be established. Previous studies by the applicant demonstrate that chronic Ang II infusions in mice cause increases in blood pressure that are associated with augmented angiotensinogen expression and the persistence of renin activity in the kidneys as well as high intrarenal Ang II content. Because is known that angiotensin-converting enzyme (ACE) is responsible for most of Ang I conversion to Ang II in the mouse kidney, this project will take advantage of recently generated tissue-specific ACE knockout mice to test the HYPOTHESIS that during Ang ll-induced hypertension, an increased angiotensinogen expression and persistent renin activity lead to an enhanced ACE-derived Ang II generation that in turn results in intrarenal Ang II augmentation, reductions on kidney function, water and sodium retention, the development of hypertension and renal injury.
SPECIFIC AIMS : During the mentored phase: 1. To determine the impact of reduced intrarenal Ang II formation, as a consequence of the lack of ACE activity in the kidneys, on intrarenal Ang II content and blood pressure during chronic Ang II infusions. 2. To determine the effects of chronic infusions of the ACE substrate Ang I on intrarenal Ang II content and blood pressure when the activity of this enzyme is present only in kidneys. During the independent phase: 3. To determine the effects of reduced intrarenal Ang II formation (as in specific aim 1) on kidney function during chronic Ang II infusions and, to determine the effects of chronic Ang I infusions on kidney function when Ang II formation is restricted to the kidneys (as in specific aim 2). 4. To determine the effects of reduced intrarenal Ang II formation (as in specific aim 1) on the development and severity of kidney injury during chronic Ang II infusions and, to determine the effects of chronic Ang I infusions on the same parameters when Ang II formation is restricted to the kidneys (as in specific aim 2).
Angiotensin II is a hormone that plays a major role in renal function, hypertension and kidney damage. This proposal seeks to improve the current understanding of the mechanisms and consequences of Angiotensin II formation in the kidneys in order to provide a rational approach for developing better diagnostic and therapeutic strategies for hypertension and a variety of kidney diseases.
