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Cited by 53Peroxisome Proliferator-Activated ReceptorsChronic Kidney Disease and DiabetesRenal Diseases and Glomerulopathies

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

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Ghosh, Siddhartha S., Gehr, Todd W.B., Ghosh, Shobha, Fakhry, Itaf, Sica, Domenic A., Lyall, Vijay, Schoolwerth, Anton C.·2003·Kidney International
DOI 10.1046/j.1523-1755.2003.00054.x
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Abstract

Background Mesangial proliferation is a key feature in the pathogenesis of a number of renal diseases and can be experimentally induced by the mitogen platelet-derived growth factor (PDGF). Mitogen-activated protein kinase (MAPK) signaling plays a key role in mesangial cell proliferation. In the present study we examined whether peroxisome proliferator-activated receptor gamma (PPARgamma) activators/ligands, thiazolidinediones such as ciglitazone, troglitazone, and rosiglitazone, can inhibit cell proliferation by modulating individual steps in the MAPK pathway.Methods Mouse mesangial cells were made quiescent and proliferation was measured following the application of PDGF. Using ciglitazone as the model compound, the mechanism of the antiproliferative effect of PPARgamma activators on MAPK and specific cell cycle regulatory proteins were examined by Western blot analysis and transfection studies.Results Ciglitazone inhibited PDGF-induced mesangial cell proliferation in a dose-dependent manner (1 to 20 micromol/L). The inhibitory effect was blocked by a peroxisome proliferator-activated receptor element (PPRE) decoy oligonucleotide, indicating that the observed effect of ciglitazone was via PPARgamma activation. Ciglitazone (1 to 20 micromol/L) did not affect extracellular signal-regulated protein kinase (ERK) activation but inhibited the activation of serum response element (SRE) by 85 +/- 6% (P < 0.01). This effect was associated with a reduction in c-fos expression (80 +/- 9%, P < 0.01). Ciglitazone (1, 10, and 20 micromol/L) also inhibited cyclin D1 expression by 37 +/- 8%, 79 +/- 15%, and 87 +/- 12%, respectively (P < 0.001 to 0.001), and p21 expression by 45 +/- 6% (P < 0.01), 61 +/- 10% (P < 0.001), and 72 +/- 8% (P < 0.001), respectively. Ciglitazone inhibited PDGF-mediated up-regulation of p27. In addition, the antiproliferative effect of ciglitazone was potentiated by PD98059, a mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor that acts at a step upstream from ERK.Conclusion These data indicate that PPARgamma activation may inhibit mesangial growth directly by affecting MAPK and cell cycle regulatory proteins. Furthermore, a MAP kinase inhibitor can potentiate the antiproliferative effect.

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  • PPAR-γ activation might affect the PDGF transduction signal by inhibiting extracellular factor-regulated kinase activity.

    “Thus, PPAR-γ activation might affect the PDGF transduction signal by inhibiting extracellular factor-regulated kinase (ERK) activity.[135]”

    From Nuclear receptors in liver fibrosis (2021) · cites this paper as [135]

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Authors
Ghosh, S. S., Gehr, T. W. B., Ghosh, S., Fakhry, I., Sica, D. A., Lyall, V., & Schoolwerth, A. C.
Affiliations
Virginia Commonwealth University (US)
Corresponding author
Schoolwerth, Anton C.
ORCID
Venue
Kidney International
Publisher
Elsevier BV
Published
2003-07
Volume
64
Issue
1
Pages
52-62
ISSN
0085-2538 (ISSN-L)
DOI
10.1046/j.1523-1755.2003.00054.x
OpenAlex
W2049330787
Cited by
53
References
41
Citations by year
2022: 2 · 2021: 1 · 2020: 2 · 2017: 1 · 2016: 2 · 2014: 1 · 2013: 2 · 2012: 1
FWCI
2.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Kidney International (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
Keywords
PPARγ, thiazolidinediones, ciglitazone, mesangial cell proliferation, platelet-derived growth factor, MAPK signaling, serum response element, c-fos, cyclin D1, p21, p27, cell cycle regulation, kidney disease, PPARγ agonists, antiproliferative activity, ERK
MeSH terms
Animals, Cell Division, Cells, Cultured, Drug Synergism, Enzyme Inhibitors, Flavonoids, Gene Expression Regulation, Glomerular Mesangium, Ligands, Phosphorylation, Platelet-Derived Growth Factor, Transcription Factors, Gene Expression, Cyclins, Genes, fos, Receptors, Cytoplasmic and Nuclear, Cell Cycle Proteins, Cyclin D1, Mitogen-Activated Protein Kinases, Tumor Suppressor Proteins, Serum Response Element, Thiazolidinediones, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Mice

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