DESCRIPTION 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.