PPARgamma ligand attenuates PDGF-induced mesangial cell proliferation: role of MAP kinase.
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.


CONCLUSIONS
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.
Ghosh
Siddhartha S
SS
Division of Nephrology, MCV Campus, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Gehr
Todd W B
TW
Ghosh
Shobha
S
Fakhry
Itaf
I
Sica
Domenic A
DA
Lyall
Vijay
V
Schoolwerth
Anton C
AC
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D016762:Genes, fos; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008024:Ligands; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology; D027602:Serum Response Element / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000494:pharmacology* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008024:Ligands; D010982:Platelet-Derived Growth Factor; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C039671:ciglitazone