Accumulation of extracellular matrix as scar material leading to tissue destruction is a central feature of progressive glomerulonephritis and other chronic fibrotic diseases involving the kidney, lung, liver, heart, skin, eye, bone marrow and central nervous system. Progressive fibrosis often destroys function of the organ as happens in endstage renal disease, pulmonary fibrosis and liver cirrhosis. Such chronic fibrotic diseases are major causes of human suffering and death, and add billions of dollars to the national cost of health care. The molecular events underlying the pathogenesis of fibrosis are not understood and, consequently there are few or no effective therapies for these disorders. Research, as proposed in this application, to elucidate the molecular basis of fibrosis is critically needed. A growing body of evidence suggests that overproduction of transforming growth factor-beta (TGF-beta), a cytokine vital to tissue repair, may be responsible for the scarring in chronic kidney diseases. Our laboratory has developed a model of progressive glomerulonephritis that closely resembles human disease. We also have developed a potential antifibrotic agent, the human proteoglycan decorin, that blocks the action of TGF-beta. In this research application we propose 1) to understand the molecular basis of TGF-beta overproduction in the disease and 2) to elucidate the mechanism of decorin's antifibrotic actions. We propose to provide this new information by accomplishing the following Specific Aims: 1) To further investigate and characterize our progressive model of glomerulonephritis, 2) To determine whether decorin's antifibrotic effect is due solely to TGF-beta binding or whether simultaneous attachment to matrix via collagen fibrils is also a requirement, 3) To determine if if decorin administration can prevent, limit or reverse sustained TGF-beta expression and progressive fibrosis in the animal model of chronic glomerulonephritis. The therapeutic efficacy of decorin will be tested at different stages in the experimental model. The results of these experiments will be invaluable in predicting the future of decorin as an antifibrotic agent. This research proposal is aimed at elucidating the pathogenesis of fibrosis and testing an experimental treatment. Our findings may offer considerable hope to those who suffer from progressive glomerulonephritis and other fibrotic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049374-02
Application #
2150104
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1994-09-30
Project End
1998-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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
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
Yu, Ling; Border, Wayne A; Anderson, Ian et al. (2004) Combining TGF-beta inhibition and angiotensin II blockade results in enhanced antifibrotic effect. Kidney Int 66:1774-84
Peters, Harm; Border, Wayne A; Ruckert, Matthias et al. (2003) L-arginine supplementation accelerates renal fibrosis and shortens life span in experimental lupus nephritis. Kidney Int 63:1382-92
Huang, Yufeng; Haraguchi, Masashi; Lawrence, Daniel A et al. (2003) A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis. J Clin Invest 112:379-88
Yu, Ling; Border, Wayne A; Huang, Yufeng et al. (2003) TGF-beta isoforms in renal fibrogenesis. Kidney Int 64:844-56
Haraguchi, M; Border, W A; Huang, Y et al. (2001) t-PA promotes glomerular plasmin generation and matrix degradation in experimental glomerulonephritis. Kidney Int 59:2146-55
Border, W A; Noble, N (2001) Maximizing hemodynamic-independent effects of angiotensin II antagonists in fibrotic diseases. Semin Nephrol 21:563-72

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