Hemolytic uremic syndrome (HUS) results from a variety of initiating factors. The central component of this syndrome which acutely determines organ dysfunction is the occurrence of endothelial injury leading to thrombi in the microcirculation. The impact of this acute thrombotic diathesis on long-term progression has, however, not been determined. These studies therefore, aim to relate mechanisms of thrombotic injury to progression. We hypothesize that progressive glomerulosclerosis after endothelial Injury reflects an imbalance in thrombotic/antiproteolytic versus anticoagulant/proteolytic activities. We further hypothesize that angiotensin II is pivotal in mediating this progression from thrombosis to fibrosis. To address the above hypotheses, we will investigate mechanisms of sclerosis in two models with early endothelial cell injury with and without thrombosis preceding the later development of sclerosis (i.e., radiation nephropathy versus 5/6 nephrectomy). Angiotensin activation is now firmly established as a mechanism in progression of renal diseases. The new facet of angiotensin actions which we will elucidate in these studies is a direct link to the coagulation cascade. Our preliminary data (in vivo in radiation nephropathy, a model with early thrombosis followed by late sclerosis) show that inhibition of angiotensin II markedly ameliorates structural injury, and also decreases expression of the antifibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1), but not of other components of the plasmin/plasminogen activator system (tissue-type and urokinase plasminogen activators). Plasminogen activator inhibitor-1 has been implicated in HUS and in models of thrombotic microangiopathy. The newly available knockout mice for plasminogen activator inhibitor-1 will allow specific assessment of the role of the plasminogen activator/plasmin system in thrombosis and progressive injury. We will therefore examine the interactions of the renin angiotensin system and the plasmin/plasminogen activator system in thrombosis and its impact on later sclerosis. Overall, these studies will define pathogenesis of thrombosis and its impact on subsequent sclerosis.
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