Integrated actions of transforming growth factor-beta1 and connective tissue growth factor in renal fibrosis

Qi, W, Twigg, S, Chen, X, Polhill, T, Poronnik, P, Gilbert, R and Pollock, C 2005, 'Integrated actions of transforming growth factor-beta1 and connective tissue growth factor in renal fibrosis', American Journal of Physiology: Renal Physiology, vol. 288, no. 4, pp. 800-809.


Document type: Journal Article
Collection: Journal Articles

Title Integrated actions of transforming growth factor-beta1 and connective tissue growth factor in renal fibrosis
Author(s) Qi, W
Twigg, S
Chen, X
Polhill, T
Poronnik, P
Gilbert, R
Pollock, C
Year 2005
Journal name American Journal of Physiology: Renal Physiology
Volume number 288
Issue number 4
Start page 800
End page 809
Total pages 10
Publisher American Physiological Society
Abstract Matrix accumulation in the renal tubulointerstitium is predictive of a progressive decline in renal function. Transforming growth factor- Beta1 (TGF-Beta1) and, more recently, connective tissue growth factor (CTGF) are recognized to play key roles in mediating the fibrogenic response, independently of the primary renal insult. Further definition of the independent and interrelated effects of CTGF and TGF-Beta1 is critical for the development of effective antifibrotic strategies. CTGF (20 ng/ml) induced fibronectin and collagen IV secretion in primary cultures of human proximal tubule cells (PTC) and cortical fibroblasts (CF) compared with control values (P < 0.005 in all cases). This effect was inhibited by neutralizing antibodies to either TGF-Beta or to the TGF-Beta type II receptor (TBetaRII). TGF-Beta1 induced a greater increase in fibronectin and collagen IV secretion in both PTC (P < 0.01) and CF (P < 0.01) compared with that observed with CTGF alone. The combination of TGF-Beta1 and CTGF was additive in their effects on both PTC and CF fibronectin and collagen IV secretion. TGF-?1 (2 ng/ml) stimulated CTGF mRNA expression within 30 min, which was sustained for up to 24 h, with a consequent increase in CTGF protein (P < 0.05), whereas CTGF had no effect on TGF-?1 mRNA or protein expression. TGF-Beta1 (2 ng/ml) induced phosphorylated (p)Smad-2 within 15 min, which was sustained for up to 24 h. CTGF had a delayed effect on increasing pSmad-2 expression, which was evident at 24 h. In conclusion, this study has demonstrated the key dependence of the fibrogenic actions of CTGF on TGF-Beta. It has further uniquely demonstrated that CTGF requires TGF-Beta, signaling through the TBetaRII in both PTCs and CFs, to exert its fibrogenic response in this in vitro model.
Subject Cell Physiology
DOI - identifier 10.1152/ajprenal.00179.2004
Copyright notice Copyright © 2005 the American Physiological Society.
ISSN 1931-857X
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