mPGES-1-Derived PGE2 Contributes to Indoxyl Sulfate-Induced Mesangial Cell Proliferation

Background/Aims: We previously reported that indoxyl sulfate (IS) could cause mesangial cell (MC) proliferation via a cyclooxygenase (COX)-2-dependent mechanism. However, the specific prostaglandin contributing to COX-2 effect on IS-induced MC proliferation remained unknown. Thus, the present study was undertaken to examine the role of microsomal prostaglandin E synthase-1 (mPGES-1)-derived Prostaglandin E2 (PGE2) in IS-induced MC proliferation. Methods: IS was administered to the MCs with or without mPGES-1 siRNA pretreatment to induce the MC proliferation which was determined by cell cycle analysis, DNA synthesis, and the expressions of cyclins. In another experimental setting, PGE2 was applied to the MCs to examine its direct effect on MC proliferation, as well as the regulation of prostaglandin E receptors (EPs) by qRT-PCR. Results: With the administration of IS, mPGES-1(not mPGES-2 and cytosolic PGES) was significantly upregulated at both protein and mRNA levels in line with a promoted MC proliferation. Interestingly, silencing mPGES-1 reduced cell number in S and G2 phases and blocked the upregulation of cyclin A2 and cyclin D1 in parallel with blunted PGE2 release after IS treatment, indicating that mPGES-1-derived PGE2 could contribute to MC proliferation. Furthermore, we confirmed that exogenous PGE2 could directly trigger the proliferative response in MCs. Lastly, we observed a selective upregulation of EP2 after PGE2 treatment and enhanced phosphorylation of NF-κB following IS administration in MCs, suggesting the potential involvements of EP2 and NF-κB in this pathological process. Conclusion: mPGES-1-derived PGE2 contributed to IS-induced mesangial cell proliferation.

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A positive feedback loop involving Erk5 and Akt turns on mesangial cell proliferation in response to PDGF

AJP Cell Physiology ◽

10.1152/ajpcell.00387.2013 ◽

2014 ◽

Vol 306 (11) ◽

pp. C1089-C1100 ◽

Cited By ~ 18

Author(s):

Amit Bera ◽

Falguni Das ◽

Nandini Ghosh-Choudhury ◽

Xiaonan Li ◽

Sanjay Pal ◽

...

Keyword(s):

Cell Proliferation ◽

Dna Synthesis ◽

Cyclin D1 ◽

Positive Feedback ◽

Mesangial Cell ◽

Mesangial Cells ◽

Pi3 Kinase ◽

Dominant Negative ◽

Mesangial Cell Proliferation

Platelet-derived growth factor BB and its receptor (PDGFRβ) play a pivotal role in the development of renal glomerular mesangial cells. Their roles in increased mesangial cell proliferation during mesangioproliferative glomerulonephritis have long been noted, but the operating logic of signaling mechanisms regulating these changes remains poorly understood. We examined the role of a recently identified MAPK, Erk5, in this process. PDGF increased the activating phosphorylation of Erk5 and tyrosine phosphorylation of proteins in a time-dependent manner. A pharmacologic inhibitor of Erk5, XMD8-92, abrogated PDGF-induced DNA synthesis and mesangial cell proliferation. Similarly, expression of dominant negative Erk5 or siRNAs against Erk5 blocked PDGF-stimulated DNA synthesis and proliferation. Inhibition of Erk5 attenuated expression of cyclin D1 mRNA and protein, resulting in suppression of CDK4-mediated phosphorylation of the tumor suppressor protein pRb. Expression of cyclin D1 or CDK4 prevented the dominant negative Erk5- or siErk5-mediated inhibition of DNA synthesis and mesangial cell proliferation induced by PDGF. We have previously shown that phosphatidylinositol 3-kinase (PI3-kinase) contributes to PDGF-induced proliferation of mesangial cells. Inhibition of PI3-kinase blocked PDGF-induced phosphorylation of Erk5. Since PI3-kinase acts through Akt, we determined the role of Erk5 on Akt phosphorylation. XMD8-92, dominant negative Erk5, and siErk5 inhibited phosphorylation of Akt by PDGF. Interestingly, we found inhibition of PDGF-induced Erk5 phosphorylation by a pharmacological inhibitor of Akt kinase and kinase dead Akt in mesangial cells. Thus our data unfold the presence of a positive feedback microcircuit between Erk5 and Akt downstream of PI3-kinase nodal point for PDGF-induced mesangial cell proliferation.

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Lysophosphatidylcholine stimulates EGF receptor activation and mesangial cell proliferation: Regulatory role of Src and PKC

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/j.bbalip.2007.09.004 ◽

2007 ◽

Vol 1771 (11) ◽

pp. 1364-1371 ◽

Cited By ~ 17

Author(s):

Babu V. Bassa ◽

Jung W. Noh ◽

Shobha H. Ganji ◽

Mi-Kyung Shin ◽

Daeyoung D. Roh ◽

...

Keyword(s):

Cell Proliferation ◽

Egf Receptor ◽

Mesangial Cell ◽

Receptor Activation ◽

Regulatory Role ◽

Mesangial Cell Proliferation

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Role of cyclin kinase inhibitor p27 in inhibition of emodin on mesangial cell proliferation induced by tumor necrosis factor-α

Journal of Chinese Integrative Medicine ◽

10.3736/jcim20040213 ◽

2004 ◽

Vol 2 (2) ◽

pp. 120-122 ◽

Cited By ~ 4

Author(s):

Xiao-Bin Mei

Keyword(s):

Cell Proliferation ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Mesangial Cell ◽

Kinase Inhibitor ◽

Mesangial Cell Proliferation ◽

Factor Α ◽

Necrosis Factor ◽

Cyclin Kinase Inhibitor

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Indoxyl Sulfate Induces Mesangial Cell Proliferation via the Induction of COX-2

Mediators of Inflammation ◽

10.1155/2016/5802973 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Shuzhen Li ◽

Sijie Cheng ◽

Zhenzhen Sun ◽

Harr-keshauve Mungun ◽

Wei Gong ◽

...

Keyword(s):

Mesangial Cell ◽

Underlying Mechanism ◽

Residual Renal Function ◽

Cell Number ◽

Indoxyl Sulfate ◽

Synthesis Rate ◽

Cycle Phase ◽

Progressive Loss ◽

Cox 2 ◽

Stage Renal Disease

Indoxyl sulfate (IS) is one of important uremic toxins and is markedly accumulated in the circulation of end stage renal disease (ESRD) patients, which might contribute to the damage of residual nephrons and progressive loss of residual renal function (RRF). Thus this study was undertaken to investigate the role of IS in modulating mesangial cell (MC) proliferation and the underlying mechanism. The proliferation of MCs induced by IS was determined by cell number counting, DNA synthase rate, and cell cycle phase analysis. COX-2 expression was examined by Western blotting and qRT-PCR, and a specific COX-2 inhibitor NS398 was applied to define its role in IS-induced MC proliferation. Following IS treatment, MCs exhibited increased total cell number, DNA synthesis rate, and number of cells in S and G2 phases paralleled with the upregulation of cyclin A2 and cyclin D1. Next, we found an inducible inflammation-related enzyme COX-2 was remarkably enhanced by IS, and the inhibition of COX-2 by NS398 significantly blocked IS-induced MC proliferation in line with a blockade of PGE2 production. These findings indicated that IS could induce MC proliferation via a COX-2-mediated mechanism, providing new insights into the understanding and therapies of progressive loss of RRF in ESRD.

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Role of coagulation factor Xa and protease-activated receptor 2 in human mesangial cell proliferation

Kidney International ◽

10.1111/j.1523-1755.2005.00317.x ◽

2005 ◽

Vol 67 (6) ◽

pp. 2123-2134 ◽

Cited By ~ 32

Author(s):

Misa Tanaka ◽

Hidenori Arai ◽

Ning Liu ◽

Fumiaki Nogaki ◽

Keiko Nomura ◽

...

Keyword(s):

Cell Proliferation ◽

Mesangial Cell ◽

Factor Xa ◽

Coagulation Factor ◽

Human Mesangial Cell ◽

Mesangial Cell Proliferation ◽

Protease Activated Receptor 2

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PPARγ ligand attenuates PDGF-induced mesangial cell proliferation: Role of MAP kinase

Kidney International ◽

10.1046/j.1523-1755.2003.00054.x ◽

2003 ◽

Vol 64 (1) ◽

pp. 52-62 ◽

Cited By ~ 43

Author(s):

Siddhartha S. Ghosh ◽

Todd W.B. Gehr ◽

Shobha Ghosh ◽

Itaf Fakhry ◽

Domenic A. Sica ◽

...

Keyword(s):

Cell Proliferation ◽

Map Kinase ◽

Mesangial Cell ◽

Mesangial Cell Proliferation

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Rapamycin at subimmunosuppressive levels inhibits mesangial cell proliferation and extracellular matrix production

AJP Renal Physiology ◽

10.1152/ajprenal.00128.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. F76-F81 ◽

Cited By ~ 16

Author(s):

Helen R. Lock ◽

Steven H. Sacks ◽

Michael G. Robson

Keyword(s):

Cell Proliferation ◽

Dna Synthesis ◽

Mechanism Of Action ◽

Mesangial Cell ◽

Mesangial Cells ◽

Primary Cultures ◽

Cell Number ◽

In Vivo Studies ◽

Dependent Manner ◽

Mesangial Cell Proliferation

In view of its proven antiproliferative effects, rapamycin offers potential in the treatment of mesangioproliferative disease. Previous data have shown an effect of rapamycin on mesangial cell proliferation at high doses and have not explored the mechanism of action. Therefore, we explored the effects and mechanism of action of low levels of rapamycin on mesangial cell proliferation. Primary cultures of mouse mesangial cells were grown in medium containing serum with differing concentrations of rapamycin. A rapamycin concentration of 0.1 ng/ml caused a decrease in cell number and DNA synthesis with no effect on apoptosis. Type IV collagen protein production was inhibited at 0.01 ng/ml rapamycin, although gene expression was unaffected. P70S6K phosphorylation was inhibited in parallel with the effects on cell number and DNA synthesis in a dose-dependent manner, but no effect was seen at 0.01 ng/ml rapamycin. These data show an effect on mesangial cell proliferation and p70S6 kinase phosphorylation of 0.1 ng/ml rapamycin and an effect on collagen IV production of 0.01 ng/ml rapamycin. We suggest that further in vivo studies should explore the potential for low-dose rapamycin in the treatment of mesangioproliferative glomerulonephritis.

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