CENTRAL ROLE OF TGF-BETA IN THE PATHOGENESIS OF DIABETIC NEPHROPATHY AND MACROVASCULAR COMPLICATIONS - A HYPOTHESIS

Patients with insulin-dependent diabetes mellitus (IDDM) and albuminur ia are at high risk for severe micro- and macrovascular complications. Diabetic vascular complications are characterized by structural alter ations of extracellular matrix (ECM) components in glomeruli and large vessel walls, namely, accumulation of collagen IV, collagen VI and fi bronectin and relative decrease of heparan sulphate proteoglycan (HSPC ). We hypothesize that the defect remodelling of ECM contributing to n ephropathy and macrovascular disease is induced by overproduction of t ransforming growth factor-beta (TGF-beta). Recent reports indicate tha t hyperglycaemia, increased intraglomerular pressure, and glycated pro teins potentially induce overproduction of TGF-beta in diabetes. TGF-b eta stimulates production of ECM components such as collagen IV, fibro nectin, proteoglycans (decorin and biglycan) without increasing HSPC. TGF-beta overproduction leads to glomerulosclerosis and TGF-beta is a causal factor in myointimal hyperplasia after balloon injury of caroti d artery. It mediates angiotensin II modulator effect on smooth muscle cell growth. These findings may indicate TGF-beta overproduction to b e a common pathogenetic step explaining the well-known association bet ween micro- and macrovascular complications in diabetic patients. TGF- beta antagonists, such as decorin, betaglycan, and possibly also hepar in, might be potential candidates for future therapy to prevent diabet ic vascular disease.