Sustained expression of thrombospondin-1 is associated with the development of glomerular and tubulointerstitial fibrosis in the remnant kidney model.
BACKGROUND/AIMS: Transforming growth factor-beta1 (TGF-beta1) has been implicated in the development of progressive nephrosclerosis in the remnant kidney model of chronic renal insufficiency. Thrombospondin-1 (TSP-1) is an extracellular matrix protein which has been recently shown to be capable of converting TGF-beta from its latent to its active form. We studied the expression of TSP-1 mRNA and protein during the development of glomerular and tubulointerstitial nephrosclerosis in the renal ablation model particularly in relation to TGF-beta1 expression. METHODS: The remnant kidney model in the rat was investigated 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 7.5 weeks and 10 weeks after disease induction. Using single and double immunostaining techniques, renal tissues were examined for TSP-1 protein, TGF-beta1, platelet-derived growth factor BB, extracellular matrix proteins, such as collagens and fibronectin, myofibroblast formation and macrophage influx. TSP-1 mRNA expression was investigated using a radioactive in situ hybridization technique. RESULTS: De novo expression of TSP-1 mRNA and protein occurred in all glomerular cell types as well as in tubular cells, myofibroblasts and some macrophages in areas of tubulointerstitial injury. TSP-1 expression preceded and was sustained during the development of tubulointerstitial and glomerular fibrosis and was frequently localized at sites of increased expression of TGF-beta1, but not of platelet-derived growth factor BB. CONCLUSION: In the remnant kidney model, the time course and localization of TSP-1 are consistent with its playing a role as a local activator of TGF-beta1, thereby potentially participating in the development of nephrosclerosis.[1]References
- Sustained expression of thrombospondin-1 is associated with the development of glomerular and tubulointerstitial fibrosis in the remnant kidney model. Hugo, C., Kang, D.H., Johnson, R.J. Nephron (2002) [Pubmed]
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