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Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis.
J Am Soc Nephrol. 2005 Jan; 16(1):133-43.JA

Abstract

Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-beta. However, its precise role in renal interstitial fibrogenesis has not yet been clarified. It was demonstrated previously that CTGF was expressed in tubular epithelial cells that had been engulfed by interstitial fibrosis in the remnant kidney of the subtotal nephrectomy (SNx) model. In the present study, co-cultures of tubular epithelial cells (mProx24) and tubulointerstitial fibroblasts (TFB) that mimic the subepithelial mesenchyme in the kidney were used to study the profibrotic effects of TGF-beta1-induced CTGF. In these co-cultures, TGF-beta1 treatment resulted in significantly increased mRNA levels of type I collagen and fibronectin in the TFB. These effects were both direct and indirect, with the latter being mediated by CTGF derived from the co-cultured mProx24. Then TGF-beta1 transgenic mice were subtotally nephrectomized and treated with CTGF antisense oligodeoxynucleotide, and their kidneys were analyzed for fibrosis. Intravenous administration of CTGF antisense oligodeoxynucleotide significantly blocked CTGF expression in the proximal tubular epithelial cells in the remnant kidney of these animals despite the sustained level of TGF-beta1 mRNA. This reduction in CTGF mRNA level paralleled a reduction in mRNA levels of matrix molecules as well as proteinase inhibitors plasminogen activator inhibitor-1 and tissue inhibitor of metalloproteinase-1, suppressing renal interstitial fibrogenesis. In conclusion, tubular CTGF acts as a downstream mediator of the profibrotic effects of TGF-beta1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-beta1-dependent interstitial fibrosis.

Authors+Show Affiliations

Department of Nephrology, Saitama Medical College, 38 Morohongo, Moroyama-machi, Irumagun, Saitama 350-0495, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

15574513

Citation

Okada, Hirokazu, et al. "Connective Tissue Growth Factor Expressed in Tubular Epithelium Plays a Pivotal Role in Renal Fibrogenesis." Journal of the American Society of Nephrology : JASN, vol. 16, no. 1, 2005, pp. 133-43.
Okada H, Kikuta T, Kobayashi T, et al. Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. J Am Soc Nephrol. 2005;16(1):133-43.
Okada, H., Kikuta, T., Kobayashi, T., Inoue, T., Kanno, Y., Takigawa, M., Sugaya, T., Kopp, J. B., & Suzuki, H. (2005). Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. Journal of the American Society of Nephrology : JASN, 16(1), 133-43.
Okada H, et al. Connective Tissue Growth Factor Expressed in Tubular Epithelium Plays a Pivotal Role in Renal Fibrogenesis. J Am Soc Nephrol. 2005;16(1):133-43. PubMed PMID: 15574513.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. AU - Okada,Hirokazu, AU - Kikuta,Tomohiro, AU - Kobayashi,Tatsuya, AU - Inoue,Tsutomu, AU - Kanno,Yoshihiko, AU - Takigawa,Masaharu, AU - Sugaya,Takeshi, AU - Kopp,Jeffrey B, AU - Suzuki,Hiromichi, Y1 - 2004/12/01/ PY - 2004/12/3/pubmed PY - 2005/6/23/medline PY - 2004/12/3/entrez SP - 133 EP - 43 JF - Journal of the American Society of Nephrology : JASN JO - J Am Soc Nephrol VL - 16 IS - 1 N2 - Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-beta. However, its precise role in renal interstitial fibrogenesis has not yet been clarified. It was demonstrated previously that CTGF was expressed in tubular epithelial cells that had been engulfed by interstitial fibrosis in the remnant kidney of the subtotal nephrectomy (SNx) model. In the present study, co-cultures of tubular epithelial cells (mProx24) and tubulointerstitial fibroblasts (TFB) that mimic the subepithelial mesenchyme in the kidney were used to study the profibrotic effects of TGF-beta1-induced CTGF. In these co-cultures, TGF-beta1 treatment resulted in significantly increased mRNA levels of type I collagen and fibronectin in the TFB. These effects were both direct and indirect, with the latter being mediated by CTGF derived from the co-cultured mProx24. Then TGF-beta1 transgenic mice were subtotally nephrectomized and treated with CTGF antisense oligodeoxynucleotide, and their kidneys were analyzed for fibrosis. Intravenous administration of CTGF antisense oligodeoxynucleotide significantly blocked CTGF expression in the proximal tubular epithelial cells in the remnant kidney of these animals despite the sustained level of TGF-beta1 mRNA. This reduction in CTGF mRNA level paralleled a reduction in mRNA levels of matrix molecules as well as proteinase inhibitors plasminogen activator inhibitor-1 and tissue inhibitor of metalloproteinase-1, suppressing renal interstitial fibrogenesis. In conclusion, tubular CTGF acts as a downstream mediator of the profibrotic effects of TGF-beta1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-beta1-dependent interstitial fibrosis. SN - 1046-6673 UR - https://www.unboundmedicine.com/medline/citation/15574513/Connective_tissue_growth_factor_expressed_in_tubular_epithelium_plays_a_pivotal_role_in_renal_fibrogenesis_ L2 - https://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=15574513 DB - PRIME DP - Unbound Medicine ER -