Antisense oligonucleotides against thrombospondin-1 inhibit activation of TGF-β in fibrotic renal disease in the rat in vivo

Daniel C, Takabatake Y, Mizui M, Isaka Y, Kawashi H, Rupprecht H, Imai E, Hugo C (2003)

Publication Language: English

Publication Type: Journal article

Publication year: 2003

Journal

American Journal of Pathology American Society for Investigative Pathology (ASIP)

Book Volume: 163

Pages Range: 1185-1192

Journal Issue: 3

DOI: 10.1016/S0002-9440(10)63478-5

Abstract

Specific treatment of chronic progressive renal disease is very limited. TGF-β, 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-β 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-β 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-β and by the inhibition of the TGF-β-dependent smad-signaling pathway, as well as transcription of TGF-β 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-β in experimental inflammatory kidney disease.

Authors with CRIS profile

Christoph Daniel Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

LMU Klinikum DE Germany (DE) Osaka University / 大阪大学 JP Japan (JP) Niigata University / 新潟大学 JP Japan (JP)

How to cite

APA:

Daniel, C., Takabatake, Y., Mizui, M., Isaka, Y., Kawashi, H., Rupprecht, H.,... Hugo, C. (2003). Antisense oligonucleotides against thrombospondin-1 inhibit activation of TGF-β in fibrotic renal disease in the rat in vivo. American Journal of Pathology, 163(3), 1185-1192. https://doi.org/10.1016/S0002-9440(10)63478-5

MLA:

Daniel, Christoph, et al. "Antisense oligonucleotides against thrombospondin-1 inhibit activation of TGF-β in fibrotic renal disease in the rat in vivo." American Journal of Pathology 163.3 (2003): 1185-1192.

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