Role of connective tissue growth factor in profibrotic action of transforming growth factor-beta: a potential target for preventing renal fibrosis.
Tubulointerstitial fibrosis is a crucial process determining the progression and prognosis of various renal diseases. Connective tissue growth factor (CTGF), a novel fibrogenic protein induced by transforming growth factor-beta (TGF-beta), is upregulated in various clinical and experimental nephropathies, but the significance of CTGF in the profibrotic action of TGF-beta is still poorly defined. To explore the implication of CTGF in renal fibrosis, we investigated gene expression of CTGF, fibronectin, and alpha1(I) collagen in an obstructive nephropathy model in rats. Furthermore, to elucidate the role of CTGF in TGF-beta-stimulated extracellular matrix accumulation, we analyzed the effects of blockade of endogenous CTGF using antisense oligodeoxynucleotides (ODNs) in cultured rat renal fibroblasts. After unilateral ureteral obstruction, TGF-beta1 and CTGF messenger RNA (mRNA) expression in the obstructed kidney was coordinately upregulated from the early stage of interstitial fibrosis, followed by marked induction of fibronectin and alpha1(I) collagen mRNA expression. In cultured normal rat kidney fibroblast (NRK-49F) cells, CTGF antisense ODN transfection significantly attenuated TGF-beta1-induced fibronectin and alpha1(I) collagen mRNA expression compared with control reverse ODNs. These results indicate that CTGF has a crucial role in the profibrotic action of TGF-beta in renal fibroblasts, providing a potential therapeutic target against tubulointerstitial fibrosis.
Yokoi
H
H
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Sugawara
A
A
Mukoyama
M
M
Mori
K
K
Makino
H
H
Suganami
T
T
Nagae
T
T
Yahata
K
K
Fujinaga
Y
Y
Tanaka
I
I
Nakao
K
K
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
C526316:CCN2 protein, rat; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D005353:Fibronectins; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D003094:Collagen