Mitogen-activated protein kinase mediates mevalonate-stimulated human mesangial cell proliferation.
The metabolic products of intracellular mevalonate (MVA) are important for the growth of eukaryotic cells. These products include cholesterol and several non-sterol isoprenoids. It has been reported that 3-hydroxy-3-methylglutaryl 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 signal-regulated kinase (ERK) inhibitor, SP600125, c-Jun NH2-teminal kinase (JNK) inhibitor, or SB203580, a P38 mitogen-activated protein kinase (MAPK) inhibitor. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl 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 factor-β1 (TGF-β1), Type IV and Type I collagen (Col-IV and Col-I). The expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), phosphorylated (p)-ERK1/2, p-JNK and p-p38 were also examined using western blot analysis. MVA significantly stimulated HMC proliferation and markedly increased the secretion of TGF-β1 and expression levels of Col-IV and Col-I. In addition, treatment with MVA significantly upregulated the expression of Bcl-2 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 TGF-β1 and the inhibition of apoptosis. These effects were mediated, at least in part, by the JNK and ERK pathways.
Department of Nephrology, Provincial People's Hospital of Shanxi Medical University, Shanxi Provincial People's Hospital, Shanxi Kidney Disease Institute, Taiyuan, Shanxi 030001, P.R. China.
Xiaoshuang
X
Zhou
Department of Pathology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
Chen
C
Wang
Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
Jihua
J
Tian
Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
Yanhong
Y
Wang
Department of Nephrology, Provincial People's Hospital of Shanxi Medical University, Shanxi Provincial People's Hospital, Shanxi Kidney Disease Institute, Taiyuan, Shanxi 030001, P.R. China.
Yafeng
Y
Li
Department of Nephrology, Baylor College of Medicine, Houston, TX 77030, USA.
Zhaoyong
Z
Hu
Department of Nephrology, Provincial People's Hospital of Shanxi Medical University, Shanxi Provincial People's Hospital, Shanxi Kidney Disease Institute, Taiyuan, Shanxi 030001, P.R. China.
Rongshan
R
Li
D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008798:Mevalonic Acid / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000873:Anthracenes; C494826:BAX protein, human; C000595707:BCL2 protein, human; D024042:Collagen Type I; D024141:Collagen Type IV; D005419:Flavonoids; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D053773:Transforming Growth Factor beta1; D051028:bcl-2-Associated X Protein; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D008798:Mevalonic Acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one