Thrombospondin 1 precedes and predicts the development of tubulointerstitial fibrosis in glomerular disease in the rat

Kidney Int. 1998 Feb;53(2):302-11. doi: 10.1046/j.1523-1755.1998.00774.x.

Abstract

Tubulointerstitial fibrosis is one of the most important histologic features that predicts progression in kidney disease. Thrombospondin 1 is an extracellular matrix protein that can activate latent TGF-beta, a cytokine implicated in the pathogenesis of tubulointerstitial fibrosis. We examined the expression of thrombospondin 1 in several animal models of glomerulonephritis (anti-Thy1 model, aminonucleoside nephrosis, passive Heymann nephritis) that are associated with tubulointerstitial disease. Thrombospondin 1 mRNA and protein were transiently increased in tubular cells, myofibroblasts and some macrophages in areas of tubulointerstitial injury. Thrombospondin 1 expression always preceded the development of tubulointerstitial fibrosis, and correlated quantitatively and spatially with the later development of interstitial fibrosis. Thrombospondin 1 expression predicted the severity of tubulointerstitial fibrosis better than the degree of macrophage or myofibroblast accumulation. Thrombospondin 1 expression was associated with increased expression and activation of TGF-beta1 and decreased expression of LAP-TGF-beta in areas of tubulointerstitial injury. We conclude that thrombospondin 1 is an early marker predicting the development of tubulointerstitial kidney disease. De novo expression of thrombospondin 1 is associated and colocalized with increased expression of TGF-beta1 and decreased expression of LAP-TGF-beta during the development of tubulointerstitial disease in vivo. These data are consistent with the possibility that thrombospondin 1 may be an endogenous activator of TGF-beta.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anticoagulants / analysis
  • Anticoagulants / metabolism
  • Becaplermin
  • Biopsy
  • Extracellular Matrix Proteins / analysis
  • Fibroblasts / pathology
  • Fibrosis
  • Gene Expression
  • Glomerular Mesangium / chemistry
  • Glomerular Mesangium / pathology*
  • Glomerulonephritis, Membranoproliferative / pathology*
  • Glomerulonephritis, Membranoproliferative / physiopathology
  • Kidney Tubules / chemistry
  • Kidney Tubules / pathology*
  • Macrophages / pathology
  • Male
  • Nephritis, Interstitial / pathology
  • Nephritis, Interstitial / physiopathology
  • Nephrosis / pathology*
  • Nephrosis / physiopathology
  • Platelet-Derived Growth Factor / analysis
  • Platelet-Derived Growth Factor / genetics
  • Predictive Value of Tests
  • Proto-Oncogene Proteins c-sis
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Thrombospondin 1 / analysis
  • Thrombospondin 1 / genetics*
  • Transforming Growth Factor beta / analysis
  • Transforming Growth Factor beta / genetics

Substances

  • Anticoagulants
  • Extracellular Matrix Proteins
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • RNA, Messenger
  • Thrombospondin 1
  • Transforming Growth Factor beta
  • Becaplermin