The mechanisms mediating kidney damage in diabetes stem from chronic hyperglycemia, but the intermediary steps are not completely understood. Evidence is accumulating that non-enzymatic glycosylation of proteins may link high glucose to diabetic kidney injury. Glycated proteins predominantly exist as Amadori products, and glycated albumin (GA) is the most abundant Amador-modified protein in serum. GA causes many of the same alterations in renal physiology as those seen in diabetic nephropathy. Our studies have shown that GA stimulates cultured mouse mesangial cells to produce excess extracellular matrix, a precursor of renal fibrosis that correlates well with decline in kidney function. The cells also make transforming growth factor- beta, a pro-sclerotic cytokine that may mediate the fibrogenic effects of GA. Protein kinase C (PKC) is up-regulated in diabetes and may signal increased mesangial TGF-beta. We hypothesize that GA participates in diabetic nephropathy increased mesangial TGF-beta. We hypothesize that GA participates in diabetic nephropathy by a mechanism that involves PKC as an intracellular signaling system and TGF-beta as a downstream effector of diabetic renal injury. Understanding the pathophysiology may yield now therapies to treat diabetic kidney disease and reduce the incidence of renal failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK009993-02
Application #
6402567
Study Section
Pathology A Study Section (PTHA)
Program Officer
Rankin, Tracy L
Project Start
2001-06-01
Project End
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
2
Fiscal Year
2001
Total Cost
$47,348
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Chen, Sheldon; Jim, Belinda; Ziyadeh, Fuad N (2003) Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up. Semin Nephrol 23:532-43
Iglesias-de la Cruz, M Carmen; Ziyadeh, Fuad N; Isono, Motohide et al. (2002) Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes. Kidney Int 62:901-13
Isono, Motohide; Chen, Sheldon; Hong, Soon Won et al. (2002) Smad pathway is activated in the diabetic mouse kidney and Smad3 mediates TGF-beta-induced fibronectin in mesangial cells. Biochem Biophys Res Commun 296:1356-65