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Am J Physiol Renal Physiol (November 9, 2004). doi:10.1152/ajprenal.00179.2004
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Submitted on May 14, 2004
Accepted on November 3, 2004

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

W. QI1, S. TWIGG2, X. CHEN1, T. S. POLHILL1, P. PORONNIK1, R. E. GILBERT3, and C. A. POLLOCK1*

1 Department of Medicine, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
2 Department of Medicine, St. Vincent's Hospital, Melbourne, VIC, Australia
3 Department of Medicine, Univerity of Queensland, St. Lucia, Queensland, Australia

* To whom correspondence should be addressed. E-mail: carpol{at}med.usyd.edu.au.

Matrix accumulation in the renal tubulointerstitium is predictive of a progressive decline in renal function. Transforming growth factor-beta1 (TGF-{beta}1), and more recently connective tissue growth factor (CTGF), are recognised to play key roles in mediating the fibrogenic response, independent of the primary renal insult. Further definition of the independent and inter-related effects of CTGF and TGF-{beta}1 is critical for the development of effective anti-fibrotic strategies. CTGF (20ng/ml) induced fibronectin and collagen IV secretion in primary cultures of human proximal tubule cells and cortical fibroblasts compared to control values (in all cases P<0.005). This effect was inhibited by neutralising antibodies to either TGF-{beta} or to the TGF-{beta} type II receptor (T{beta}RII). TGF-{beta}1 induced a greater increase in fibronectin and collagen IV secretion in both PTC (P<0.01) and CF (P<0.01) compared to that observed with CTGF alone. The combination of TGF-{beta}1 and CTGF were additive in their effects on both PTC and CF fibronectin and collagen IV secretion. TGF-{beta}1 (2ng/ml) stimulated CTGF mRNA expression within 30 min, which was sustained up to 24 hrs, with a consequent increase in CTGF protein (P<0.05) whilst CTGF had no effect on TGF-{beta}1 mRNA or protein expression. TGF-{beta}1 (2ng/ml) induced phosphorylated Smad-2 within 15 min, which was sustained up to 24 hrs. CTGF had a delayed effect on increasing pSmad-2 expression, which was evident at 24 hrs. 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}, signalling through the T{beta}RII in both PTCs and CFs, to exert its fibrogenic response in this in vitro model.




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