title: Connective tissue growth factor and regulation of the mesangial cell cycle: role in cellular hypertrophy.
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 G(1) phase from G(0), but they do not then progress further through the cell cycle. The molecular mechanisms underlying this G(1) phase arrest appear to be due to the induction of the cyclin-dependent kinase inhibitors (CDKI) p15(INK4), p21(Cip1), and p27(Kip1), 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-beta (TGF-beta)-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.
authors.affiliation: Cell and Molecular Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, South Kensington, London, United Kingdom.
authors.forename: Nadia
authors.initials: N
authors.lastname: Abdel-Wahab
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Weston
authors.forename: Terry
authors.initials: T
authors.lastname: Roberts
authors.forename: Roger M
authors.initials: RM
authors.lastname: Mason
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000378:metabolism; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000378:metabolism; D016193:G1 Phase; D005920:Glomerular Mesangium / Q000473:pathology*; D006801:Humans; D006984:Hypertrophy; D017874:Immediate-Early Proteins / Q000494:pharmacology / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C526317:CCN2 protein, human; D016213:Cyclins; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D055513:Connective Tissue Growth Factor; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases