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Integrated actions of transforming growth factor-₁ and connective tissue growth factor in renal fibrosis

¹Department of Medicine, Kolling Institute, University of Sydney, and Royal North Shore Hospital, Sydney; ²Department of Medicine, University of Sydney, and Royal Prince Alfred Hospital, Sydney; ³Department of Medicine, St. Vincent's Hospital, Melbourne; and ⁴School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia

Submitted 14 May 2004 ; accepted in final form 3 November 2004

Matrix accumulation in the renal tubulointerstitium is predictive of a progressive decline in renal function. Transforming growth factor-₁ (TGF-₁) 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-₁ 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- or to the TGF- type II receptor (TRII). TGF-₁ 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-₁ 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-₁ (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-. It has further uniquely demonstrated that CTGF requires TGF-, signaling through the TRII in both PTCs and CFs, to exert its fibrogenic response in this in vitro model.

proximal tubule cells; cortical fibroblasts; fibronectin; collagen IV; Smad-2

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