Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis

Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis Abstract Connective tissue growth factor (CTGF) is one of the candidate factors mediating downstream events of transforming growth factor-β (TGF-β), but its role in fibrogenic properties of TGF-β and in tubulointerstitial fibrosis has not yet been clarified. Using unilateral ureteral obstruction (UUO) in rats, we analyzed gene expression of TGF-β1, CTGF, and fibronectin. We further investigated the effect of blockade of endogenous CTGF on TGF-β-induced fibronectin expression in cultured rat renal fibroblasts by antisense oligodeoxynucleotide (ODN) treatment. After UUO, CTGF mRNA expression in the obstructed kidney was significantly upregulated subsequent to TGF-β1, followed by marked induction of fibronectin mRNA. By in situ hybridization, CTGF mRNA was detected mainly in the interstitial fibrotic areas and tubular epithelial cells as well as in parietal glomerular epithelial cells in the obstructed kidney. The interstitial cells expressing CTGF mRNA were also positive for α-smooth muscle actin. CTGF antisense ODN transfected into cultured renal fibroblasts significantly attenuated TGF-β-stimulated upregulation of fibronectin mRNA and protein compared with control ODN transfection, together with inhibited synthesis of type I collagen. With the use of a reporter assay, rat fibronectin promoter activity was increased by 2.5-fold with stimulation by TGF-β1, and this increase was abolished with antisense CTGF treatment. Thus CTGF plays a crucial role in fibronectin synthesis induced by TGF-β, suggesting that CTGF blockade could be a possible therapeutic target against tubulointerstitial fibrosis. transforming growth factor-β in situ hybridization obstructive nephropathy antisense oligonucleotide reporter assay Footnotes This work was supported in part by research grants from the Japanese Ministry of Education, Science, Sports, and Culture, the Japanese Ministry of Health and Welfare, “Research for the Future (RFTF)” of the Japan Society for the Promotion of Science, the Smoking Research Foundation, and the Salt Science Research Foundation. Address for reprint requests and other correspondence: M. Mukoyama, Dept. of Medicine and Clinical Science, Kyoto Univ. Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507 (E-mail: muko@kuhp.kyoto-u.ac.jp ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 10.1152/ajprenal.00122.2001 Copyright © 2002 the American Physiological Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Renal Physiology The American Physiological Society

Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis

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Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0363-6127
eISSN
1522-1466
DOI
10.1152/ajprenal.00122.2001
Publisher site
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Abstract

Abstract Connective tissue growth factor (CTGF) is one of the candidate factors mediating downstream events of transforming growth factor-β (TGF-β), but its role in fibrogenic properties of TGF-β and in tubulointerstitial fibrosis has not yet been clarified. Using unilateral ureteral obstruction (UUO) in rats, we analyzed gene expression of TGF-β1, CTGF, and fibronectin. We further investigated the effect of blockade of endogenous CTGF on TGF-β-induced fibronectin expression in cultured rat renal fibroblasts by antisense oligodeoxynucleotide (ODN) treatment. After UUO, CTGF mRNA expression in the obstructed kidney was significantly upregulated subsequent to TGF-β1, followed by marked induction of fibronectin mRNA. By in situ hybridization, CTGF mRNA was detected mainly in the interstitial fibrotic areas and tubular epithelial cells as well as in parietal glomerular epithelial cells in the obstructed kidney. The interstitial cells expressing CTGF mRNA were also positive for α-smooth muscle actin. CTGF antisense ODN transfected into cultured renal fibroblasts significantly attenuated TGF-β-stimulated upregulation of fibronectin mRNA and protein compared with control ODN transfection, together with inhibited synthesis of type I collagen. With the use of a reporter assay, rat fibronectin promoter activity was increased by 2.5-fold with stimulation by TGF-β1, and this increase was abolished with antisense CTGF treatment. Thus CTGF plays a crucial role in fibronectin synthesis induced by TGF-β, suggesting that CTGF blockade could be a possible therapeutic target against tubulointerstitial fibrosis. transforming growth factor-β in situ hybridization obstructive nephropathy antisense oligonucleotide reporter assay Footnotes This work was supported in part by research grants from the Japanese Ministry of Education, Science, Sports, and Culture, the Japanese Ministry of Health and Welfare, “Research for the Future (RFTF)” of the Japan Society for the Promotion of Science, the Smoking Research Foundation, and the Salt Science Research Foundation. Address for reprint requests and other correspondence: M. Mukoyama, Dept. of Medicine and Clinical Science, Kyoto Univ. Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507 (E-mail: muko@kuhp.kyoto-u.ac.jp ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 10.1152/ajprenal.00122.2001 Copyright © 2002 the American Physiological Society

Journal

AJP - Renal PhysiologyThe American Physiological Society

Published: May 1, 2002

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