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Ring-Sp1 decoy oligonucleotide effectively suppresses extracellular matrix gene expression and fibrosis of rat kidney induced by unilateral ureteral obstruction

Gene Therapy volume 13, pages 430–439 (2006)Cite this article

Abstract

Tubulointerstitial fibrosis is the consequence of an injury characterized by the accumulation of excess collagen and other extracellular matrix components, resulting in the destruction of the normal kidney architecture and subsequent loss of function. A transcription factor Sp1, originally described as a ubiquitous transcription factor, is involved in the basal expression of extracelluar matrix genes and may, therefore, be important in fibrotic processes. Here, we report on the design of a ring-Sp1 decoy oligonucleotide, containing the consensus Sp1 binding sequence in a single decoy molecule without an open end, to create a novel therapeutic strategy for fibrosis. The ring-Sp1 decoy oligonucleotide is highly resistant to degradation by nucleases or serum compared to the conventional phosphorothioated double-stranded Sp1 decoy oligonucleotide, and effectively suppressed the expression of transforming growth factor-β1 and fibronectin, the binding of Sp1 to the promoter region of these genes, and proliferation in response to serum in normal rat kidney fibroblasts. Moreover, treatment with the ring-Sp1 decoy in vivo significantly attenuates extracellular matrix gene expression in the rat kidney in which a unilateral ureteral obstruction had been induced. These results suggest that the ring-Sp1 decoy oligonucleotide represents promising therapeutic alternative to the conventional treatment of fibrotic disorders.

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Abbreviations

ECM:

extracellular matrix

FN:

fibronectin

GAPDH:

glyceraldehydes-3-phosphate dehydrogenase

HVJ:

hemagglutinating virus of Japan

M-Sp1 decoy:

mutated Sp1 decoy

ODN:

oligodeoxynucleotide

PBS:

phophate buffered saline

PS-Sp1 decoy:

phosphorothioate Sp1 decoy

α-SMA:

α-smooth muscle actin

SSC:

standard saline citrate

R-Sp1 decoy:

ring Sp1 decoy

TGF-β1:

transforming growth factor-β1

TNF-α:

tumore necrosis factor-α

uPA:

urokinase-type plasminogen activator

UUO:

unilateral ureteral obstruction

VEGF:

vascular endothelial growth factor.

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Acknowledgements

This work was supported by the Korea Science and Engineering Foundation (KOSEF) through the MRC for Cardiovascular Diseases and Natural products, Dongguk University (2005).

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Authors and Affiliations

  1. Department of Pathology, Catholic University of Daegu School of Medicine, Daegu, Korea

    Y-M Chae, K-K Park & Y-C Chang

  2. Cardiovascular Medical Research Center and National Research Laboratory for Glycobiology, Dongguk University, Kyungbuk, Korea

    Y-M Chae, J-K Kim & C-H Kim

  3. Department of Endocrinology, School of Medicine, Kyungpook National University, Daegu, Korea

    I-K Lee

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Chae, YM., Park, KK., Lee, IK. et al. Ring-Sp1 decoy oligonucleotide effectively suppresses extracellular matrix gene expression and fibrosis of rat kidney induced by unilateral ureteral obstruction. Gene Ther 13, 430–439 (2006). https://doi.org/10.1038/sj.gt.3302696

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