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Potentiation of TNF-–Stimulated Group IIA Phospholipase A₂ Expression by Peroxisome Proliferator–Activated Receptor Activators in Rat Mesangial Cells

Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.

Correspondence to Dr. Marietta Kaszkin, Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai-7, D-60590 Frankfurt am Main, Germany. Phone: 49-69-6301-6955; Fax: 49-69-6301-7942; E-mail: kaszkin{at}em.uni-frankfurt.de

ABSTRACT. Natural activators of peroxisome proliferator–activated receptors (PPAR) are lipid metabolites, including those produced by phospholipases A₂ (PLA₂). In glomerular mesangial cells, the secreted group IIA PLA₂ (sPLA₂-IIA), which is thought to be a crucial factor in pathologic processes in the kidney, may provide free fatty acids and eicosanoids directly or indirectly, by activating a cytosolic PLA₂. The scope of this study was to investigate whether synthetic PPAR activators have an effect on sPLA₂-IIA mRNA expression in rat mesangial cells, thus constituting a feedback modulation of sPLA₂-IIA transcription. In the presence of tumor necrosis factor– (TNF-), the PPAR agonists WY14643 and LY171883 as well as the lipid-lowering compound clofibrate potentiated expression, secretion, and activity of group IIA sPLA₂ in mesangial cells. MK886, known as a noncompetitive inhibitor of PPAR, completely abolished the potentiation of sPLA₂-IIA secretion and activity by WY14643, thus indicating that the effect of WY14643 is specifically mediated by PPAR. When cells were transfected with different constructs of the rat sPLA₂-IIA promoter fused to a luciferase reporter gene, a stimulation with TNF- in the presence of the PPAR activators caused an enhanced promoter activity compared with that induced by TNF- alone. Site-directed mutagenesis of a putative PPRE site in the sPLA₂-IIA promoter abolished the potentiating effect of PPAR agonists, thus strongly indicating its contribution to the enhanced promoter activity. In summary, this study shows that the rat sPLA₂-IIA promoter is sensitive to PPAR agonists, which act synergistically with cytokines, resulting in an enhanced expression of sPLA₂-IIA in rat mesangial cells.

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