ALTERATIONS OF GLOMERULAR MATRIX PROTEINS IN THE PATHOGENESIS OF DIABETIC NEPHROPATHY

Diabetic late complications are characterized by morphological and bio chemical alterations of the extracellular matrix. In particular, longs tanding diabetes causes quantitative and qualitative changes in baseme nt membrane structure of retinal and renal capilleries. Immunohistoche mical investigations of diabetic kidneys with diffuse glomeruloscleros is show increased collagen type IV deposition in the mesangial matrix and decreased heparan sulfate proteoglycan content in the mesangial ma trix and glomerular basement membrane as well. In nodular glomeruloscl erosis normal basement membrane components are decreased or absent whi le the occurrence of collagen type III in this stage has been interpre ted as an irreversible alteration of the glomerular structure. These c hanges seem to be the underlying cause for the alterations in renal fu nctions like persistent albuminuria and proteinuria. Increased intra- and extracellular levels of glucose and its derivatives are thought to be responsible for diabetic tissue dysfunction although there are rep orts on possible genetic defects causing increased susceptibility to d evelop diabetic nephropathy. Recent results, however, focuse on the ro le of glucose-induced cytokine secretion as mediator for altered metab olism of glomerular matrix proteins. In vitro studies with cultured ki dney cells have shown that the glucose-induced dysregulation of the ba sement membrane synthesis may be mediated by a glucose dependent activ ation of protein kinase C. Alternatively or synergistically, the forma tion of AGE products formed after prolonged exposure of matrix protein s to elevated glucose may also lead to cytokine secretion subsequently inducing synthesis of extracellular matrix proteins. Studies in exper imental animals confirm the diabetes induced dysregulation of the synt hesis of extracellular matrix components on the molecular level.