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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK060508-05A1
Application #
7148725
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Flessner, Michael Francis
Project Start
2002-03-01
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
5
Fiscal Year
2006
Total Cost
$210,530
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Zhang, Jiandong; Gu, Chunyan; Noble, Nancy A et al. (2011) Combining angiotensin II blockade and renin receptor inhibition results in enhanced antifibrotic effect in experimental nephritis. Am J Physiol Renal Physiol 301:F723-32
Huang, Yufeng; Border, Wayne A; Lawrence, Daniel A et al. (2009) Mechanisms underlying the antifibrotic properties of noninhibitory PAI-1 (PAI-1R) in experimental nephritis. Am J Physiol Renal Physiol 297:F1045-54
Zhang, Jiandong; Noble, Nancy A; Border, Wayne A et al. (2008) Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells. Am J Physiol Endocrinol Metab 295:E810-9
Huang, Yufeng; Border, Wayne A; Yu, Ling et al. (2008) A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy. J Am Soc Nephrol 19:329-38
Huang, Wei; Xu, Chen; Kahng, Kyoung W et al. (2008) Aldosterone and TGF-beta1 synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells. Am J Physiol Renal Physiol 294:F1287-95
Huang, Yufeng; Noble, Nancy A (2007) PAI-1 as a target in kidney disease. Curr Drug Targets 8:1007-15
Huang, Y; Noble, N A; Zhang, J et al. (2007) Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int 72:45-52
Huang, Y; Border, W A; Lawrence, D A et al. (2006) Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis. Kidney Int 70:515-22
Huang, Y; Wongamorntham, S; Kasting, J et al. (2006) Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int 69:105-13
Gaedeke, Jens; Noble, Nancy A; Border, Wayne A (2005) Curcumin blocks fibrosis in anti-Thy 1 glomerulonephritis through up-regulation of heme oxygenase 1. Kidney Int 68:2042-9

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