Antisense oligonucleotides against thrombospondin-1 inhibit activation of tgf-beta in fibrotic renal disease in the rat in vivo.
Specific treatment of chronic progressive renal disease is very limited. TGF-beta, considered as the major cytokine causing tissue scarring, must be activated extracellularly before it can bind to its receptors. Thrombospondin-1 (TSP1) has been identified as an activator of latent TGF-beta in in vitro systems and in pancreas and lung homeostasis in mouse pups in vivo, but whether this is also true in inflammatory fibrotic disease is unknown. We examined a rat model of mesangial proliferative glomerulonephritis, where TGF-beta has been demonstrated to mediate renal fibrosis. In this study, antisense phosphorothioate oligonucleotides against TSP1 were successfully transferred into almost all glomeruli of perfused diseased kidneys and markedly inhibited de novo synthesis of TSP1. This effect was accompanied by decreased activation but not expression of TGF-beta and by the inhibition of the TGF-beta-dependent smad-signaling pathway, as well as transcription of TGF-beta target genes such as EDA-fibronectin, resulting in a markedly suppressed accumulation of extracellular matrix. In sharp contrast, neither glomerular cell proliferation nor influx of macrophages was affected by this therapy in experimental mesangial proliferative glomerulonephritis. These results demonstrate that TSP1 is the major endogenous activator of TGF-beta in experimental inflammatory kidney disease.
Daniel
Christoph
C
Division of Nephrology, Universität Erlangen-Nürnberg, Loschgestrasse 8, 91054 Erlangen, Germany.
Takabatake
Yoshitugu
Y
Mizui
Masayuki
M
Isaka
Yoshitaka
Y
Kawashi
Hiroshi
H
Rupprecht
Harald
H
Imai
Enyu
E
Hugo
Christian
C
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D015432:Glomerulonephritis, Membranoproliferative / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism*
D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta