Angiotensin converting enzyme inhibitors (ACEI) show superior efficacy over other antihypertensives in both human and experimental progressive renal diseases. However, the precise site, i.e. local or systemic actions, of angiotensin (Ang)-dependent mechanisms of glomerulosclerosis have not been defined. for this purpose, DNA recombinant mice with ~regional~ Ang receptor gene knock-out developed in our Center will be used. These newly developed chimeric mice have patchy areas within the same kidney that express or do not express the AT type 1A receptor gene. This model thus provides a powerful tool for direct testing of the role of local renin angiotensin system actions linked to the AT1A receptor. versus systemic effects of Ang in the development of sclerosis. This receptor has been chosen since it is the predominant receptor responsible for angiotensin~s vasoconstriction and matrix accumulation effects. It is important to note, however, that inhibition of Ang does not have equal efficacy in all disease, or at late stages of disease. Indeed, even in the absence of Ang, vascular and glomerular matrix increases occur, as demonstrated in angiotensinogen knock-out mice in our laboratory. These observations point to not only Ang- sensitive but also Ang-insensitive mechanisms of fibrosis. In this connection, matrix accumulation results from both increase synthesis and decreased degradation. We will therefore test the hypothesis that the balance of matrix promoting vs. degrading mechanisms changes at different stages of sclerosis. We postulate that Ang dependent synthesis of ECM occurs in glomeruli at all stages of sclerosis. However, the progressive scarring that is resistant to ACEI is hypothesized to reflect decreased ECM degradation that is not dependent on Ang. Thus we will use the chimeric AT1A regional knockout mouse as a tool to establish Ang- dependent and -independent mechanisms and local vs. systemic actions of Ang in development of glomerulosclerosis.

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Vanderbilt University Medical Center
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