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 that accumulates in fibrotic diseases may provide useful adjuncts to therapies targeting key """"""""upstream"""""""" regulators of matrix production. The subject of this application is a new mutant of human plasminogen activator type-1 (PAI-1R) that does not inhibit proteases. Preliminary data from our laboratories using the Anti-thy-1 model of glomerulonephritis in the rat indicate that systemic administration of PAI-1R significantly increases glomerular plasmin generation and reduces markers of disease. The long-term goal of the proposed studies 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, three mechanisms. 1). Injected PAl-1 R binds to vitronectin in matrix at the site of fibrosis. Unlike native PAl-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 matrix and enhances conversion of latent to active metalloproteinases that in turn directly degrade matrix proteins. 2). The generated plasmin degrades fibrin, enhancing turnover of the provisional fibnn matrix which, in turn, diminishes replacement of this matrix by mature, pathological matrix containing fibronectin, proteoglycans and collagens. 3). PAI-1R inhibits influx of the inflammatory cells that enhance matrix production and deposition. When PAl-1 binds to vitronectin 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 whether, and to what extent, each of these mechanisms underlie the observed therapeutic effect. They use two powerful and well-studied in vivo models of renal fibrosis; Anti-thy-1 glomerulonephritis in the rat and unilateral ureteral obstruction in the mouse and a powerful panel of well-established markers of fibrotic renal disease. They use a panel of PAl-1 mutants with different characteristics in terms of stability, protease binding and vitronectin binding that have been thoroughly characterized in vitro. PAl-1-deficient (PAI-1-/ PAI-1-) and fibrinogen deficient (fib-lfib-) mice and their normal littermates will be used also. These studies will greatly further our understanding of a promising and novel therapeutic approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060508-04
Application #
6826237
Study Section
General Medicine B Study Section (GMB)
Program Officer
Flessner, Michael Francis
Project Start
2002-03-01
Project End
2006-07-31
Budget Start
2005-01-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$270,127
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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