Fibrotic renal diseases, including diabetic nephropathy, represent a major health care problem because of their prevalence and the fact that available therapies merely slow progression to renal failure. Recently, we have asked whether drugs designed to enhance degradation of the pathological matrix (ECM) that accumulates in fibrotic diseases may provide useful adjuncts to therapies targeting key """"""""upstream"""""""" regulators of ECM production. The subject of this application is a mutant of human plasminogen activator type-1 (PAI-1R) that does not inhibit proteases. We have shown systemic administration of PAI-1R ameliorates disease in anti-thy-1 nephritis in the rat. The long-term goal is to understand the mechanism(s) that underlie the therapeutic action of PAI-1R. We hypothesize that PAI-1R is therapeutic in fibrotic renal disease by one, or a combination of, four mechanisms. 1). Injected PAI-1R competes with native PAI-1 for vitronectin (Vn) binding sites at the site of fibrosis. Unlike native PAI-1, PAI-1R does not inhibit plasminogen conversion to plasmin. Thus, plasmin generation at the site of fibrosis is increased. This plasmin directly degrades pathological ECM and enhances conversion of latent to active metalloproteinases that in turn directly degrade ECM proteins. 2). The generated plasmin degrades fibrin, enhancing turnover of the provisional fibrin ECM which, in turn, diminishes replacement of this ECM by mature, pathological ECM. 3). PAI-1R inhibits influx of the inflammatory cells that enhance ECM production and deposition. When PAI-1 binds to Vn at the site of inflammation it renders inaccessible the RGD binding site required for cell attachment and migration. The studies proposed are designed to determine to what extent each of these mechanisms underlie the observed therapeutic effect. They use two powerful in vivo models of renal diabetic nephropathy: the db/db mouse model of Type II diabetes and the streptozotocin-induced diabetic nephropathy in the mouse, a powerful panel of well-established markers of fibrotic renal disease and PAI-1 (PAI-1/ PAI-1), plasminogen-(plg/plg), fibrinogen- (fib/fib) and vitronectin (Vn-Vn-)-deficient mice. These studies will further our understanding of the general promise of therapies aimed to enhance degradation of fibrotic matrix and may lead to clinical trials of a new therapeutic for diabetic nephropathy. ? ? ?
Showing the most recent 10 out of 12 publications
