Sustained expression of thrombospondin-1 is associated with the development of glomerular and tubulointerstitial fibrosis in the remnant kidney model.
OBJECTIVE
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.


CONCLUSIONS
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.
Hugo
Christian
C
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Germany.
Kang
Duk-Hee
DH
Johnson
Richard J
RJ
D000818:Animals; D000077214:Becaplermin; D004195:Disease Models, Animal; D005355:Fibrosis / Q000503:physiopathology*; D017403:In Situ Hybridization; D007678:Kidney Glomerulus / Q000166:cytology / Q000473:pathology*; D007684:Kidney Tubules / Q000166:cytology / Q000473:pathology*; D008297:Male; D009400:Nephrosclerosis / Q000503:physiopathology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D000077214:Becaplermin