The cytokine transforming growth factor-B (TGF-B) is a key biological mediator of extracellular matrix deposition in health and in fibrotic diseases, especially of the kidney. We have demonstrated a central role for TGF-B in'the pathogenesis of experimental and/or human forms of acute and chronic glomerulonephritis, diabetic nephropathy, hypertensive nephropathy,acute and chronic allograft rejection, cyclosporine nephropathy and HTV-associated nephropathy. TGF-B is also implicated in numerous fibrotic disorders involving other tissues and organs and is considered to be a principal target for designing novel therapeutic agents to block fibrotic disease.. An important question is whatis the cause of the persistent TGF-B overexpression that leads to progressive fibrosis and kidney failure? In the course of our work we have discovered a complex interconnection between TGF-B and the renin-angiotensin system (RAS) in the kidney.The RAS acts to stimulate the production and activation of TGF-B and to increase the expression of TGF-B receptors which greatly enhances TGF-B's fibrotic effects. We hypothesize that continued stimulation of TGF-Jl by the RAS may be a molecular mechanism for the continued overexpression of TGF-fi in kidney diseases. In this application we propose to investigate the molecular interconnections by which the RAS may perpetuate the actions of TGF-B and to explore in vivo therapeutic strategies to block these effects by doing the following: /) Investigate a molecular mechanism by which angiotensin II may up-regulate TGF-fi receptors by analyzing the functional elements of the TGF-fi type I receptor promoter in the kidney, 2) Investigate the possibility that renin orprorenin may be up-stream effectors that, especially in the presence of angiotensin II blockade, induce TGF-J3 overexpression and thus contribute to progressive fibrotic disease and 3) Continue investigation of the role of interactions between the renin-angiotensin system, TGF-ft overexpression and TGF-fi receptor expression in the pathogenesis of fibrosis using a model ofacute glomerulonephritis and to compare the findings with parallel studies in a model of chronic glomerulonephritis. The significance of this application is that it will apply new knowledge and technology to an area of investigation mat is directly relevant to improved understanding of the pathogenesis of kidney fibrosis and will likely provide insights that suggest new therapeutic strategies to prevent progressive kidney failure in humanssuffering from kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK043609-18
Application #
7281978
Study Section
Special Emphasis Panel (NSS)
Program Officer
Ketchum, Christian J
Project Start
1990-09-30
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
18
Fiscal Year
2007
Total Cost
$526,099
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; Wu, Jie; Gu, Chunyan et al. (2012) Receptor-mediated nonproteolytic activation of prorenin and induction of TGF-ýý1 and PAI-1 expression in renal mesangial cells. Am J Physiol Renal Physiol 303:F11-20
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
Zhang, Jiandong; Noble, Nancy A; Border, Wayne A et al. (2010) Infusion of angiotensin-(1-7) reduces glomerulosclerosis through counteracting angiotensin II in experimental glomerulonephritis. Am J Physiol Renal Physiol 298:F579-88
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, 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

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