Thrombospondin 1 precedes and predicts the development of tubulointerstitial fibrosis in glomerular disease in the rat. 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-β, 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-β1 and decreased expression of LAP-TGF-β 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-β1 and decreased expression of LAP-TGF-β 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-β.