Induction of Connective Tissue Growth Factor by Activation of Heptahelical Receptors

Hahn, Angelika F.; Heusinger‐Ribeiro, Juliane; Lanz, T.; Zenkel, Susanne; Goppelt‐Struebe, Margarete

doi:10.1074/jbc.m000976200

Cited by 100 publications

(97 citation statements)

References 54 publications

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“…CTGF induction by LPA in mesangial cells was shown to be mediated by the small GTPase rhoA and the downstream kinase ROCK. 31 Interestingly, treatments with ROCK inhibitors have been described to attenuate UUO-induced renal TIF, 33 similar to what we observed in LPA 1 (Ϫ/Ϫ)-and in Ki16425-treated mice.…”

Section: Discussionsupporting

confidence: 70%

“…Similar observations were made previously in renal fibroblasts and mesangial cells. 29,31,32 Our results show that the action of LPA on CTGF expression is very likely mediated by the BASIC RESEARCH www.jasn.org LPA 1 receptor subtype because Ki16425 blocks these effects. Consequently, the parallel between in vivo and in vitro experiments suggests that the profibrogenic effect of LPA could in part be mediated by increased CTGF expression and secretion.…”

Section: Discussionmentioning

confidence: 85%

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LPA1 Receptor Activation Promotes Renal Interstitial Fibrosis

Pradère

Klein²,

Grès

et al. 2007

Journal of the American Society of Nephrology

186

145

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Tubulointerstitial fibrosis in chronic renal disease is strongly associated with progressive loss of renal function. We studied the potential involvement of lysophosphatidic acid (LPA), a growth factor-like phospholipid, and its receptors LPA 1-4 in the development of tubulointerstitial fibrosis (TIF). Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) for up to 8 d, and kidney explants were prepared from the distal poles to measure LPA release into conditioned media. After obstruction, the extracellular release of LPA increased approximately 3-fold. Real-time reverse transcription PCR (RT-PCR) analysis demonstrated significant upregulation in the expression of the LPA 1 receptor subtype, downregulation of LPA 3 , and no change of LPA 2 or LPA 4 . TIF was significantly attenuated in LPA 1 (Ϫ/Ϫ) mice compared to wild-type littermates, as measured by expression of collagen III, ␣-smooth muscle actin (␣-SMA), and F4/80. Furthermore, treatment of wild-type mice with the LPA 1 antagonist Ki16425 similarly reduced fibrosis and significantly attenuated renal expression of the profibrotic cytokines connective tissue growth factor (CTGF) and transforming growth factor ␤ (TGF␤). In vitro, LPA induced a rapid, dose-dependent increase in CTGF expression that was inhibited by Ki16425. In conclusion, LPA, likely acting through LPA 1 , is involved in obstruction-induced TIF. Therefore, the LPA 1 receptor might be a pharmaceutical target to treat renal fibrosis.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 85%

LPA1 Receptor Activation Promotes Renal Interstitial Fibrosis

Pradère

Klein²,

Grès

et al. 2007

Journal of the American Society of Nephrology

186

145

View full text Add to dashboard Cite

show abstract

“…Analysis of unilateral ureteral obstructed kidneys displaying advanced stages of tubulointersitital fibrosis revealed a twofold increase in the in vivo level of Ctgf mRNA (24,73). Furthermore, TGF-␤ 1 stimulation of tubular epithelial cells resulted in approximately a twofold mRNA increase (24), which was similar to that observed for other cell types, including mesangial cells (22), cardiac fibroblasts (4), and corneal fibroblasts (13). These findings would suggest that a twofold increase in Ctgf mRNA level is sufficient to exert a pathophysiological effect.…”

Section: Discussionsupporting

confidence: 59%

Hypoxic induction ofCtgfis directly mediated by Hif-1

Higgins

Biju²,

Akai³

et al. 2004

American Journal of Physiology-Renal Physiology

255

196

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CTGF plays a significant role in the development of renal fibrosis by mediating the fibrotic effects of transforming growth factor (TGF)-β1and has been shown to be hypoxia inducible in human breast cancer cells. It has been suggested that hypoxia is an important underlying cause for the development of renal fibrosis through the modulation of profibrotic genes. One of the key mediators of the cell's response to lowered oxygen environments is hypoxia-inducible-factor-1 (HIF-1), a basic helix-loop-helix transcription factor, which enables cells to adapt to hypoxia by regulating the expression of genes involved in increasing oxygen availability ( VEGF, erythropoietin) and enhancing glucose uptake and metabolism ( Glut-1, PGK). In this paper, we have used primary tubular epithelial cell cultures from a tetracycline-inducible- Hif- 1α knockout murine model to further elucidate the role of Hif-1 in the hypoxic-induction of Ctgf expression. We show that hypoxia response elements present upstream of Ctgf enable direct interaction of Hif-1 transcription factor with the Ctgf promoter, resulting in increased transcription of Ctgf mRNA. Cells deficient in Hif- 1α were incapable of inducing Ctgf mRNA in response to hypoxia, suggesting an absolute requirement of Hif-1. Furthermore, the observed Hif-1-mediated hypoxic stimulation of Ctgf expression was found to occur independently of TGF-β1signaling. Our findings have important implications for a number of fibrotic disorders in which hypoxia, CTGF, and TGF-β1are involved, including renal, dermal, hepatic, and pulmonary fibrosis.

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“…CCN2 is a member of the CCN family, which plays an important role in a variety of cell processes including angiogenesis, chondrogenesis and wound healing (10,11). Findings of previous studies provided strong evidence that CCN2 plays a role in scars, particularly as a co-factor of TGF-β1 (12). In addition, CCN2 is likely to mediate the ability of TGF-β1 to stimulate ECM synthesis and is a moderate inducer of collagen synthesis (11,13).…”

Section: Introductionmentioning

confidence: 95%

Effects of CCN3 on fibroblast proliferation, apoptosis and extracellular matrix production

Ren

Hou

et al. 2014

International Journal of Molecular Medicine

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Abstract. CCN2 and CCN3 belong to the CCN family of proteins, which show a high level of structural similarity. Previous studies have shown that CCN2 mediates the ability of transforming growth factor (TGF)-β to stimulate collagen synthesis, leading to keloid formation. CCN2 and CCN3 are opposing factors in regulating the promoter activity and secretion of this extracellular matrix (ECM) protein. Thus, we hypothesize that CCN3 possesses an anti-scarring effect. However, the exact mechanism of CCN3 in this anti-scarring effect remains unclear. The aim of this study was to investigate the mechanism of CCN3 in reducing scar formation. Palatal fibroblasts were obtained from the explants of the oral palatal mucosa of 8-week-old male Sprague-Dawley rats. CCN3 overexpression vector was constructed and then transfected into cells. The inhibitory effects of CCN3 on cell growth were detected via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was measured using an Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) apoptosis detection kit and flow cytometry. The expression levels of collagen I, collagen III and α-smooth muscle actin (α-SMA) were determined by western blot analysis and RT-PCR. Following treatment with TGF-β1, we detected the expression of CCN3 and Smad1 in the fibroblasts. CCN3 significantly inhibited the growth and induction of apoptosis of fibroblasts. The expression of collagen I, collagen III and α-SMA was lower in the CCN3-transfected group as compared to the control and vector groups. TGF-β1 stimulation efficiently suppressed the expression of CCN3 at the mRNA and protein levels, and CCN3 was required for TGF-β1-induced Smad1 phosphorylation. Results of this study demonstrated that CCN3 is involved in the proliferation and apoptosis of fibroblasts and the synthesis of ECM proteins. Therefore, CCN3 may play an important role in the development of scar tissue, and may represent a novel therapeutic target for reducing scar formation.

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Induction of Connective Tissue Growth Factor by Activation of Heptahelical Receptors

Cited by 100 publications

References 54 publications

LPA1 Receptor Activation Promotes Renal Interstitial Fibrosis

LPA1 Receptor Activation Promotes Renal Interstitial Fibrosis

Hypoxic induction ofCtgfis directly mediated by Hif-1

Effects of CCN3 on fibroblast proliferation, apoptosis and extracellular matrix production

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