Hormones – Cytokines – Signaling
Kidney International (2003) 64, 52–62; doi:10.1046/j.1523-1755.2003.00054.x
PPAR
ligand attenuates PDGF-induced mesangial cell proliferation: Role of MAP kinase
Siddhartha S Ghosh, Todd W B Gehr, Shobha Ghosh, Itaf Fakhry, Domenic A Sica, Vijay Lyall and Anton C Schoolwerth
Division of Nephrology, MCV Campus, Virginia Commonwealth University, Richmond, Virginia
Correspondence: Anton C. Schoolwerth, Division of Nephrology, MCV Campus, Virginia Commonwealth University, Box 980160, Richmond, VA 23298. E-mail: aschoolw@mail2.vcu.edu
Received 26 April 2002; Revised 12 December 2002; Re-revised 27 January 2003; Accepted 24 February 2003.
Abstract
PPAR
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 (PPAR
) 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 PPAR 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 
mol/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 PPAR activation. Ciglitazone (1 to 20 mol/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 mol/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 PPAR activation may inhibit mesangial growth directly by affecting MAPK and cell cycle regulatory proteins. Furthermore, a MAP kinase inhibitor can potentiate the antiproliferative effect.
Keywords:
AP-1, decoy oligonucleotide, ciglitazone, cyclin D1
