The overall objectives of this project are: 1) to examine the effect of streptozotocin-diabetes on the biochemistry of basement membrane components; 2) to study the effect of diabetes on the in vivo synthesis and turnover of specific collagen and non-collagen moieties of glomerular basement membrane; 3) to evaluate the effect of insulin treatment on changes in basement membrane metabolism identified in the foregoing studies; and 4) to examine the manner in which glucose and growth hormone modulate glomerular and lens capsule basement membrane synthesis and structure-function relationships. Glomerular and lens capsule basement membranes will be purified from control, streptozotocin-diabetic, and growth hormone or insulin treated rats, either after in vivo radiotracer injection or incubation in vitro of isolated glomeruli or lenses with appropriate radiolabeled precursor. In vivo studies will follow the biosynthesis and turnover of procollagen, proteoglycan, and glycoprotein. In vitro studies will assess the effect of glucose and growth hormone on the production specific basement membrane components including glycosaminoglycan, laminin, and entactin. Analytic studies will probe the manner in which increased non-enzymatic glycosylation in diabetes influences basement membrane organization by examining collagen cross-link formation, solubility, polymerization, and lysyloxidase-catalyzed aldehyde formation. The results of these studies are expected to advance our understanding of the pathogenesis of diabetic microangiopathy and of the defects in the capillary filtration barrier which contribute to complications of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038308-02
Application #
3237586
Study Section
Pathology A Study Section (PTHA)
Project Start
1986-07-01
Project End
1988-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University City Science Center
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ziyadeh, F N; Han, D C; Cohen, J A et al. (1998) Glycated albumin stimulates fibronectin gene expression in glomerular mesangial cells: involvement of the transforming growth factor-beta system. Kidney Int 53:631-8
Ziyadeh, F N; Cohen, M P; Guo, J et al. (1997) RAGE mRNA expression in the diabetic mouse kidney. Mol Cell Biochem 170:147-52
Cohen, M P; Ziyadeh, F N (1996) Role of Amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy. J Am Soc Nephrol 7:183-90
Cohen, M P; Hud, E; Wu, V Y et al. (1995) Glycated albumin modified by Amadori adducts modulates aortic endothelial cell biology. Mol Cell Biochem 143:73-9
Cohen, M P; Hud, E; Wu, V Y et al. (1995) Albumin modified by Amadori glucose adducts activates mesangial cell type IV collagen gene transcription. Mol Cell Biochem 151:61-7
Cohen, M P; Sharma, K; Jin, Y et al. (1995) Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy. J Clin Invest 95:2338-45
Wu, V Y; Cohen, M P (1995) Evidence for a ligand receptor system mediating the biologic effects of glycated albumin in glomerular mesangial cells. Biochem Biophys Res Commun 207:521-8
Cohen, M P; Vasselli, J R; Neuman, R G et al. (1995) Treatment with acarbose, an alpha-glucosidase inhibitor, reduces increased albumin excretion in streptozotocin-diabetic rats. Gen Pharmacol 26:1355-61
Wu, V Y; Cohen, M P (1994) Receptors specific for Amadori-modified glycated albumin on murine endothelial cells. Biochem Biophys Res Commun 198:734-9
Cohen, M P; Hud, E; Wu, V Y (1994) Amelioration of diabetic nephropathy by treatment with monoclonal antibodies against glycated albumin. Kidney Int 45:1673-9

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