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From the Division of Nephrology,* Universität Erlangen-Nürnberg, Erlangen, Germany; Medizinische Poliklinik, LMU University, Munich, Germany; the Institute of Nephrology, Niigata University School of Medicine, Asahimachi-dori, Niigata, Japan; and the 1st Department of Medicine, University School of Medicine, Osaka, Japan
Specific treatment of chronic progressive renal disease is very limited. TGF-ß, 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-ß 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-ß 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-ß and by the inhibition of the TGF-ß-dependent smad-signaling pathway, as well as transcription of TGF-ß 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-ß in experimental inflammatory kidney disease.
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