Abstract
Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-β. 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-β1-induced CTGF. In these co-cultures, TGF-β1 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-β1 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-β1 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-β1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-β1-dependent interstitial fibrosis.
| Original language | English |
|---|---|
| Pages (from-to) | 133-143 |
| Number of pages | 11 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 16 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2005 |
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ASJC Scopus subject areas
- Nephrology
Cite this
Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. / Okada, Hirokazu; Kikuta, Tomohiro; Kobayashi, Tatsuya; Inoue, Tsutomu; Kanno, Yoshihiko; Takigawa, Masaharu; Sugaya, Takeshi; Kopp, Jeffrey B.; Suzuki, Hiromichi.
In: Journal of the American Society of Nephrology, Vol. 16, No. 1, 2005, p. 133-143.Research output: Contribution to journal › Article
}
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
PY - 2005
Y1 - 2005
N2 - Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-β. 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-β1-induced CTGF. In these co-cultures, TGF-β1 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-β1 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-β1 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-β1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-β1-dependent interstitial fibrosis.
AB - Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-β. 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-β1-induced CTGF. In these co-cultures, TGF-β1 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-β1 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-β1 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-β1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-β1-dependent interstitial fibrosis.
UR - http://www.scopus.com/inward/record.url?scp=21044454845&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=21044454845&partnerID=8YFLogxK
U2 - 10.1681/ASN.2004040339
DO - 10.1681/ASN.2004040339
M3 - Article
C2 - 15574513
AN - SCOPUS:21044454845
VL - 16
SP - 133
EP - 143
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 1
ER -