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Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro.
Cell Biol Int. 2004; 28(12):863-73.CB

Abstract

Connective tissue growth factor (CTGF) has been reported to play an important role in mediating the profibrotic effects of transforming growth factor-beta (TGF-beta) in various renal diseases. To elucidate the role of CTGF in renal tubular epithelial-myofibroblast transdifferentiation, we examined the expression of alpha-smooth muscle actin (alpha-SMA), vimentin, tenascin-C, and collagen IV expression upon the stimulation of CTGF in cultured human proximal tubular epithelial cell line (HKC), and further investigated the effects of endogenous CTGF blockade on the transdifferentiation process induced by TGF-beta. It is revealed that upon the stimulation of recombinant human CTGF (rhCTGF, 2.5 or 5.0 microg/L), the expression of alpha-SMA and tenascin-C mRNA increased significantly (p<0.01), while collagen IV gene expression decreased significantly (p<0.01), all in a dose-dependent manner. The percentage of alpha-SMA-positive cells was significantly larger in the rhCTGF-stimulated groups than that in negative control (38.9%, 65.5% vs. 2.4%, respectively, p<0.01) as confirmed by flow cytometry. Both cytoplasmic and secretory tenascin-C expression was upregulated by the stimulation of rhCTGF (p<0.01). Under this condition, collagen IV secreted into the culture media was lowered markedly (p<0.01). On RT-PCR analysis, TGF-beta1 upregulated CTGF gene expression, preceding that of alpha-SMA. The alpha-SMA mRNA expression induced by TGF-beta1 was significantly inhibited by CTGF antisense oligodeoxynucleotide (ODN) transfection (p<0.01). With prolonged incubation time, CTGF antisense ODN also inhibited intracellular alpha-SMA protein synthesis, as demonstrated by indirect immuno-fluorescence. So it is concluded that CTGF could promote the transdifferentiation of human renal tubular epithelial cells towards myofibroblasts in vitro, both directly and as a downstream mediator of TGF-beta, and CTGF blockade would be a possible therapeutic target against tubulointerstitial fibrosis.

Authors+Show Affiliations

Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. zhangchun1234@126.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15566956

Citation

Zhang, Chun, et al. "Connective Tissue Growth Factor Regulates the Key Events in Tubular Epithelial to Myofibroblast Transition in Vitro." Cell Biology International, vol. 28, no. 12, 2004, pp. 863-73.
Zhang C, Meng X, Zhu Z, et al. Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro. Cell Biol Int. 2004;28(12):863-73.
Zhang, C., Meng, X., Zhu, Z., Liu, J., & Deng, A. (2004). Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro. Cell Biology International, 28(12), 863-73.
Zhang C, et al. Connective Tissue Growth Factor Regulates the Key Events in Tubular Epithelial to Myofibroblast Transition in Vitro. Cell Biol Int. 2004;28(12):863-73. PubMed PMID: 15566956.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro. AU - Zhang,Chun, AU - Meng,Xianfang, AU - Zhu,Zhonghua, AU - Liu,Jianshe, AU - Deng,Anguo, PY - 2004/07/13/received PY - 2004/08/31/revised PY - 2004/09/07/accepted PY - 2004/11/30/pubmed PY - 2005/6/1/medline PY - 2004/11/30/entrez SP - 863 EP - 73 JF - Cell biology international JO - Cell Biol Int VL - 28 IS - 12 N2 - Connective tissue growth factor (CTGF) has been reported to play an important role in mediating the profibrotic effects of transforming growth factor-beta (TGF-beta) in various renal diseases. To elucidate the role of CTGF in renal tubular epithelial-myofibroblast transdifferentiation, we examined the expression of alpha-smooth muscle actin (alpha-SMA), vimentin, tenascin-C, and collagen IV expression upon the stimulation of CTGF in cultured human proximal tubular epithelial cell line (HKC), and further investigated the effects of endogenous CTGF blockade on the transdifferentiation process induced by TGF-beta. It is revealed that upon the stimulation of recombinant human CTGF (rhCTGF, 2.5 or 5.0 microg/L), the expression of alpha-SMA and tenascin-C mRNA increased significantly (p<0.01), while collagen IV gene expression decreased significantly (p<0.01), all in a dose-dependent manner. The percentage of alpha-SMA-positive cells was significantly larger in the rhCTGF-stimulated groups than that in negative control (38.9%, 65.5% vs. 2.4%, respectively, p<0.01) as confirmed by flow cytometry. Both cytoplasmic and secretory tenascin-C expression was upregulated by the stimulation of rhCTGF (p<0.01). Under this condition, collagen IV secreted into the culture media was lowered markedly (p<0.01). On RT-PCR analysis, TGF-beta1 upregulated CTGF gene expression, preceding that of alpha-SMA. The alpha-SMA mRNA expression induced by TGF-beta1 was significantly inhibited by CTGF antisense oligodeoxynucleotide (ODN) transfection (p<0.01). With prolonged incubation time, CTGF antisense ODN also inhibited intracellular alpha-SMA protein synthesis, as demonstrated by indirect immuno-fluorescence. So it is concluded that CTGF could promote the transdifferentiation of human renal tubular epithelial cells towards myofibroblasts in vitro, both directly and as a downstream mediator of TGF-beta, and CTGF blockade would be a possible therapeutic target against tubulointerstitial fibrosis. SN - 1065-6995 UR - https://www.unboundmedicine.com/medline/citation/15566956/Connective_tissue_growth_factor_regulates_the_key_events_in_tubular_epithelial_to_myofibroblast_transition_in_vitro_ L2 - https://doi.org/10.1016/j.cellbi.2004.09.003 DB - PRIME DP - Unbound Medicine ER -