Mitogen-activated protein kinase mediates mevalonate-stimulated human mesangial cell proliferation
- Authors:
- Xiaoshuang Zhou
- Chen Wang
- Jihua Tian
- Yanhong Wang
- Yafeng Li
- Zhaoyong Hu
- Rongshan Li
View Affiliations
Affiliations: 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, Department of Pathology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China, Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China, Department of Nephrology, Baylor College of Medicine, Houston, TX 77030, USA
- Published online on: May 4, 2015 https://doi.org/10.3892/mmr.2015.3715
-
Pages:
2643-2649
-
Copyright: © Zhou
et al. This is an open access article distributed under the
terms of Creative
Commons Attribution License [CC BY_NC 3.0].
Metrics: Total
Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
This article is mentioned in:
Abstract
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.
View Figures |
Figure 1
|
 |
Figure 2
|
 |
Figure 3
|
 |
Figure 4
|
 |
Figure 5
|
 |
Figure 6
|
 |
Figure 7
|
 |
Figure 8
|
View References
|
1
|
Chiang CK, Sheu ML, Hung KY, Wu KD and Liu
SH: Honokiol, a small molecular weight natural product, alleviates
experimental mesangial proliferative glomerulonephritis. Kidney
Int. 70:682–689. 2006. View Article : Google Scholar : PubMed/NCBI
|
|
2
|
Kim SI, Na HJ, Ding Y, et al: Autophagy
promotes intracellular degradation of type I collagen induced by
transforming growth factor (TGF)-β1. J Biol Chem. 287:11677–11688.
2012. View Article : Google Scholar : PubMed/NCBI
|
|
3
|
Zeng R, Xiong Y, Zhu F, et al: Fenofibrate
attenuated glucose-induced mesangial cells proliferation and
extracellular matrix synthesis via PI3K/AKT and ERK1/2. PLoS One.
8:e768362013. View Article : Google Scholar : PubMed/NCBI
|
|
4
|
Owens TW, Foster FM, Valentijn A, Gilmore
AP and Streuli CH: Role for X-linked Inhibitor of apoptosis protein
upstream of mitochondrial permeabilization. J Biol Chem.
285:1081–1088. 2010. View Article : Google Scholar :
|
|
5
|
Kennedy DJ, Chen Y, Huang W, et al: CD36
and Na/K-ATPase-α1 form a proinflammatory signaling loop in kidney.
Hypertension. 61:216–224. 2013. View Article : Google Scholar
|
|
6
|
Jougasaki M, Ichiki T, Takenoshita Y and
Setoguchi M: Statins suppress interleukin-6-induced monocyte
chemoattractant protein-1 by inhibiting Janus kinase/signal
transducers and activators of transcription pathways in human
vascular endothelial cells. Br J Pharmacol. 159:1294–1303. 2010.
View Article : Google Scholar : PubMed/NCBI
|
|
7
|
Cassidy H, Radford R, Slyne J, et al: The
role of MAPK in drug induced kidney injury. J Signal Transduct.
2012:4636172012.
|
|
8
|
Feliers D and Kasinath BS: Erk in kidney
diseases. J Signal Transduct. 2011:7685122011.PubMed/NCBI
|
|
9
|
Huang K, Liu W, Lan T, et al: Berberine
reduces fibronectin expression by suppressing the S1P-S1P2 receptor
pathway in experimental diabetic nephropathy models. PLoS One.
7:e438742012. View Article : Google Scholar : PubMed/NCBI
|
|
10
|
Wang W, He B, Shi W, Liang X, Ma J, et al:
Deletion of scavenger receptor A protects mice from progressive
nephropathy independent of lipid control during diet-induced
hyperlipidemia. Kidney Int. 81:1002–1014. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
11
|
Zhang Y, Kong J, Deb DK, Chang A and Li
YC: Vitamin D receptor attenuates renal fibrosis by suppressing the
rennin-angiotensin system. J Am Soc Nephrol. 21:966–973. 2010.
View Article : Google Scholar : PubMed/NCBI
|
|
12
|
Xiao HB, Liu RH, Ling GH, Xiao L, Xia YC,
et al: HSP47 regulates ECM accumulation in renal proximal tubular
cells induced by TGF-β1 through ERK1/2 and JNK MAPK pathways. Am J
Physiol Renal Physiol. 303:F757–765. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
13
|
Linkermann A, Chen G, Dong G, Kunzendorf
U, Krautwald S and Dong Z: Regulated cell death in AKI. J Am Soc
Nephrol. 25:2689–2701. 2014. View Article : Google Scholar : PubMed/NCBI
|
|
14
|
Kondoh K, Sunadome K and Nishida E: Notch
signaling suppresses p38 MAPK activity via induction of MKP-1 in
myogenesis. J Biol Chem. 282:3058–3065. 2007. View Article : Google Scholar
|
|
15
|
Yang C, Patel K, Harding P, et al:
Regulation of TGF-beta1/MAPK-mediated PAI-1 gene expression by the
actin cytoskeleton in human mesangial cells. Exp Cell Res.
313:1240–1250. 2007. View Article : Google Scholar : PubMed/NCBI
|
|
16
|
Kim SI, Kwak JH, Na HJ, Kim JK, Ding Y and
Choi ME: Transforming growth factor-beta (TGF-beta1) activates TAK1
via TAB1-mediated autophosphorylation, independent of TGF-beta
receptor kinase activity in mesangial cells. J Biol Chem.
284:22285–22296. 2009. View Article : Google Scholar : PubMed/NCBI
|
