Mitogen-activated protein kinase mediates mevalonate-stimulated human mesangial cell proliferation

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E-ISSN： 1791-3004|12|2|2643-2649

ISSN： 1791-2997

Source： Molecular Medicine Reports, Vol.12, Iss.2, 2015-01, pp. : 2643-2649

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Abstract

The metabolic products of intracellular mevalonate (MVA) are important for the growth of eukaryotic cells. These products include cholesterol and several nonsterol isoprenoids. It has been reported that 3hydroxy3methylglutaryl coenzyme A reductase inhibitors ameliorate glomerular injury in several experimental models of progressive glomerular disease by inhibiting the production of MVA and its metabolites. However, the mechanisms by which MVA stimulates the growth of human mesangial cells (HMCs) remain to be elucidated. To investigate the role of MVA in HMC proliferation, apoptosis, cell cycle and accumulation of extracellular matrix (ECM), the effects of MVA on HMCs at different durations and at various doses were evaluated. To examine the mechanisms of the effects of MVA on HMCs, the cells were treated with MVA, with or without PD98059, an extracellular signalregulated kinase (ERK) inhibitor, SP600125, cJun NH2teminal kinase (JNK) inhibitor, or SB203580, a P38 mitogenactivated protein kinase (MAPK) inhibitor. A 3(4,5dimethylthiazol2yl)2,5diphenyl tetrazolium bromide reduction assay was used to measure the proliferation of the HMCs, a flow cytometric assay was used to assess the proliferative index, and an ELISA was performed to determine the expression of transforming growth factorβ1 (TGFβ1), Type and Type I collagen (Col and ColI). The expression of Bcell lymphoma 2 (Bcl2), Bcl2associated X protein (Bax), phosphorylated (p)ERK1/2, pJNK and pp38 were also examined using western blot analysis. MVA significantly stimulated HMC proliferation and markedly increased the secretion of TGFβ1 and expression levels of Col and ColI. In addition, treatment with MVA significantly upregulated the expression of Bcl2 and suppressed the expression of Bax in the HMCs. These responses were partially inhibited by the addition of inhibitors of ERK or JNK, however, they were not inhibited by the p38 MAPK inhibitor. These results demonstrated that MVA promoted HMC proliferation and ECM protein expression, which were associated with an increase in the expression of TGFβ1 and the inhibition of apoptosis. These effects were mediated, at least in part, by the JNK and ERK pathways.