Increased glomerular alpha 1 (IV) collagen expression and deposition in long-term diabetic rats is prevented by chronic glycosaminoglycan treatment.

Diabetic nephropathy is associated with thickening of the glomerular basement membrane and, in particular, with mesangial matrix expansion. Previous studies have indicated that administration of chemically modified, low-anticoagulant heparins prevents some of the morphologic and physiologic alterations occurring in experimental diabetic nephropathy. The effect of prolonged heparin treatment on the glomerular expression and deposition of alpha 1 (IV) collagen, which is a major component of the mesangial matrix, has not been reported previously. Four groups of rats were studied for 12 months: two control groups and two groups of streptozotocin-diabetic rats. One group in each branch received modified heparin continuously from the induction of diabetes. After 12 months synthesis and deposition of alpha 1 (IV) collagglomerula and adjacent tubuli were determined by nonradioactive in situ hybridization and immunohistochemistry. Mesangial cells were localized by Thy 1.1 staining. Long-term diabetes caused a significant increase in alpha 1 (IV) collagen deposition in the mesangial matrix and a more than 2-fold enhancement of glomerular cell alpha 1 (IV) collagen transcript levels, mainly in mesangial cells. The alpha 1 (IV) collagen mRNA levels of proximal tubular cells and visceral epithelial cells were similarly increased. Chronic treatment of diabetic rats with modified heparin completely prevented the increased alpha 1 (IV) collagen deposition and expression. The increased glomerular deposition of alpha 1 (IV) collagen observed in long-term streptozotocin diabetic rats appears to depend on an increased alpha 1 (IV) collagen synthesis. Because chronic application of low-anticoagulant heparin completely prevents the increased alpha 1 (IV) collagen synthesis by mesangial cells, this result suggests a new therapeutic option for the prevention of diabetic nephropathy in humans.