Thrombospondin-1 is a major activator of TGF-beta in fibrotic renal disease in the rat in vivo.
BACKGROUND
Transforming growth factor-beta (TGF-beta), a profibrotic cytokine involved in many scarring processes, has to be activated extracellularly before it can bind to its receptors. Thrombospondin 1 (TSP1), a multifunctional matricellular glycoprotein, has been identified as an activator of TGF-beta in in vitro systems and during mouse postnatal development in vivo. TSP1 is expressed de novo in many inflammatory disease processes, including glomerular disease.


METHODS
In this study we investigated whether peptides specifically interfering with the activation process of TGF-beta by TSP1 may be able to block activation of TGF-beta in an in vivo model of mesangial proliferative glomerulonephritis.


RESULTS
Continuous intravenous infusion of blocking peptide by minipumps significantly reduced expression of active TGF-beta in glomeruli on day 7 of disease as indicated by immunohistochemistry, bioassay, and activation of the TGF-beta signal transduction pathway, while total TGF-beta expression was unchanged. Inhibition of glomerular TGF-beta activation was accompanied by a decrease of glomerular extracellular matrix accumulation and proteinuria, but was without effect on mesangial cell proliferation or influx of monocytes/macrophages.


CONCLUSIONS
TSP1 is a major endogenous activator of TGF-beta in experimental inflammatory glomerular disease. Drugs interfering with the activation of TGF-beta by locally produced TSP1 may be considered as a future specific treatment of scarring kidney disease.
Daniel
Christoph
C
Division of Nephrology, Universität Erlangen-Nürnberg, Erlangen, Germany.
Wiede
Julia
J
Krutzsch
Henry C
HC
Ribeiro
Solange M F
SM
Roberts
David D
DD
Murphy-Ullrich
Joanne E
JE
Hugo
Christian
C
D000818:Animals; D002455:Cell Division; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology*; D007518:Isoantibodies; D008264:Macrophages / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2
D007518:Isoantibodies; C487834:Leu-Ser-Lys-Leu peptide; D010455:Peptides; D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; C035678:anti-Thy antibody