Abstract

This is a joint proposal from an experimental nephrology group and a group working on extracellular matrix molecular biology to study the accumulation of the extracellular matrix (ECM) in diabetic kidney disease. Synthesis of ECM components will be studied in a glomerular organ culture system previously used by this group in establishing the central role of transforming growth factor-beta (TGF-Beta) in the deposition of ECM into nephritic glomeruli. Antibodies to ECM components associated with increased TGF-Beta activity, wound healing and complement activity will be used to characterize the specific features of the diabetic glomerular matrix in a rat diabetes model and in samples from patients. The expression of proteoglycans, various forms of ECM glycoproteins, with integrin-type receptors for ECM, and various forms of TGF-Beta will be evaluated with antibodies and molecular probes. If evidence for the involvement of TGF-Beta in the pathogenesis of diabetic kidney disease is obtained, suppression of the syndrome with specific antibodies and other substances capable of blocking TGF-Beta activity will be attempted. Alternative pathogenetic mechanisms for the matrix accumulation in diabetic kidney disease will also be considered. These studies will provide new molecular information on the structure of the diabetic glomerular ECM and may lead to understanding of the pathogenetic mechanisms of the ECM accumulation as well as point to ways of preventing it.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK043609-03
Application #
3244986
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1990-09-30
Project End
1995-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

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

Showing the most recent 10 out of 58 publications