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

Lab Invest. 1996 Feb;74(2):484-95.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • Collagen / antagonists & inhibitors*
  • Collagen / genetics
  • Collagen / metabolism
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Drug Administration Schedule
  • Glycosaminoglycans / administration & dosage*
  • Glycosaminoglycans / pharmacology
  • Heparin / pharmacology
  • In Situ Hybridization
  • Kidney Glomerulus / metabolism*
  • Kidney Glomerulus / pathology
  • Male
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Glycosaminoglycans
  • RNA, Messenger
  • Heparin
  • Collagen