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CTGF Mediates TGF-–Induced Fibronectin Matrix Deposition by Upregulating Active 51 Integrin in Human Mesangial Cells

Cell and Molecular Biology Section, Division of Biomedical Sciences, Imperial College School of Medicine, London, United Kingdom.

Correspondence to Dr. Roger M. Mason, Cell and Molecular Biology Section, Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK. Phone: +44-20-7594-43019; Fax: 44-20-7594-3015;

ABSTRACT. Excessive deposition of fibronectin in the glomerular mesangium in diabetic nephropathy (DN) is partly due to the induction of transforming growth factor- (TGF-) by high glucose. TGF- induces its downstream mediator connective tissue growth factor (CTGF), which stimulates fibronectin matrix synthesis, a process that requires the presence of 51 integrin. Although TGF- has been shown to upregulate 51 integrin expression in human mesangial cells (HMC), little is known about the effect of CTGF on levels of this receptor. This study tested whether CTGF modulates 51 expression by HMC in culture and whether changes induced by TGF- are mediated through the induction of CTGF. FACS analysis showed that both TGF- and CTGF significantly increased cell-surface 51 levels compared with basal conditions. RT-PCR indicated that the changes were at the level of transcription. Treatment of cells with TGF- and antisense CTGF oligonucleotides significantly reduced the TGF-–induced increases in 51 levels. CTGF and TGF- also significantly increased levels of ligand-occupied cell-surface 1 integrins and cell adhesion to fibronectin, the main 51 substrate. Antisense CTGF significantly reduced the number of adherent cells from TGF-–stimulated cultures. Finally, 51 blocking antibodies inhibited HMC fibronectin matrix deposition, confirming the importance of this receptor for this process. Taken together, these data provide evidence that CTGF controls 51 expression by HMC in vitro. Alterations in 51 levels induced by TGF- are mediated at least in part through the induction of CTGF, and specific targeting of either 51 or CTGF could be useful in controlling excessive fibronectin matrix production in DN. E-mail roger.mason@ic.ac.uk

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