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| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
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Cell and Molecular Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, South Kensington, London, United Kingdom.
Correspondence to Dr. Roger M. Mason, Cell and Molecular Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, South Kensington, London, SW7 2AZ, UK. Phone: 0044-20-7594-3019; Fax: 0044-20-7594-3015;
ABSTRACT. Connective tissue growth factor (CTGF) is now considered to be one of the important driver molecules for the pathogenesis of diabetic nephropathy (DN) and possibly many other fibrotic disorders. However, the molecular mechanisms by which CTGF functions remain to be established. In an attempt to define these mechanisms, this study was designed to investigate whether CTGF has any effect on the cell cycle of human mesangial cells (HMC), which are known to undergo hypertrophy in DN. This report provides the first evidence that CTGF is a hypertrophic factor for HMC. CTGF stimulates HMC to actively enter the G1 phase from G0, but they do not then progress further through the cell cycle. The molecular mechanisms underlying this G1 phase arrest appear to be due to the induction of the cyclin-dependent kinase inhibitors (CDKI) p15INK4, p21Cip1, and p27Kip1, which are known to bind and inactivate cyclinD/CDK4/6 and the cyclin E/CDK2 kinase complexes. This could account for the maintenance of pRb protein in a non- or very low-phosphorylated state, preventing cell cycle progression. Using CTGF antisense oligonucleotides, the results also indicate that the previously identified transforming growth factor–
(TGF-)–induced hypertrophy in mesangial cells is CTGF-dependent. Mesangial cell hypertrophy is one of the earliest abnormalities of diabetic nephropathy; therefore, therapeutic strategies targeting CTGF may be beneficial in controlling DN. Email: roger.mason@ic.ac.uk
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