Our previous work indicates that angiotensin induces expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of fibrinolysis and matrix degradation, in vitro and in vivo. A causal link between angiotensin and PAI-1 and sclerosis is supported by our in vivo demonstration that inhibition of angiotensin II (AII) selectively decreases expression of PAI-1, and that high doses of either a type 1 AII receptor antagonist, or angiotensin I converting enzyme inhibitor (ACEI) can even lead to resolution of existing, biopsy-proven sclerosis in the rat in the 5/6 nephrectomy model of progressive glomerulosclerosis. Based on these data, we hypothesize that inhibition of angiotensin II and PAI-1, by promoting matrix degradation and modulating cell growth/differentiation, is pivotal in resolution of sclerosis. The available mutant mice strains have so far not been utilized to examine mechanisms of progression of renal disease because of a lack of success in applying established models of progressive renal disease in the mouse. We now have in hand a model of progressive glomerulosclerosis in the mouse, which will be applied to the newly available mutant mice strains deficient for or overexpressing components of the plasmin/plasminogen activator system, that provide a unique opportunity to study mechanisms of resolution of sclerosis. We also have available a specific inhibitor of PAI-1, which will allow additional, time specific inhibition of PAI-1 and determination of its contribution to sclerosis and its reversal in vivo. We will use in vivo models together with in vitro experiments to examine the interactions of the renin angiotensin system and the plasmin/plasminogen activator system in sclerosis and its resolution.
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