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 b asement membrane and, in particular, with mesangial matrix expansion. Previous studies have indicated that administration of chemically modi fied, 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 expressi on 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 mo dified heparin continuously from the induction of diabetes. After 12 m onths synthesis and deposition of alpha 1(IV) collagglomerula and adja cent tubuli were determined by nonradioactive in situ hybridization an d immunohistochemistry. Mesangial cells were localized by Thy 1.1 stai ning. Long-term diabetes caused a significant increase in alpha 1(IV) collagen deposition in the mesangial matrix and a more than 2-fold enh ancement of glomerular cell alpha 1(IV) collagen transcript levels, ma inly in mesangial cells. The alpha 1(IV) collagen mRNA levels of proxi mal tubular cells and visceral epithelial cells were similarly increas ed. Chronic treatment of diabetic rats with modified heparin completel y prevented the increased alpha 1(IV) collagen deposition and expressi on. The increased glomerular deposition of alpha 1(IV) collagen observ ed in long-term streptozotocin diabetic rats appears to depend on an i ncreased alpha 1(IV) collagen synthesis. Because chronic application o f 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 human s.