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. Natural activators of peroxisome proliferator–activated receptors (PPAR) are lipid metabolites, including those produced by phospholipases A 2  (PLA 2 ). In glomerular mesangial cells, the secreted group IIA PLA 2  (sPLA 2 -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 PLA 2 . The scope of this study was to investigate whether synthetic PPARα activators have an effect on sPLA 2 -IIA mRNA expression in rat mesangial cells, thus constituting a feedback modulation of sPLA 2 -IIA transcription. In the presence of tumor necrosis factor–α (TNF-α), the PPARα agonists WY14643 and LY171883 as well as the lipid-lowering compound clofibrate potentiated expression, secretion, and activity of group IIA sPLA 2  in mesangial cells. MK886, known as a noncompetitive inhibitor of PPARα, completely abolished the potentiation of sPLA 2 -IIA secretion and activity by WY14643, thus indicating that the effect of WY14643 is specifically mediated by PPARα. When cells were transfected with different constructs of the rat sPLA 2 -IIA promoter fused to a luciferase reporter gene, a stimulation with TNF-α in the presence of the PPARα activators caused an enhanced promoter activity compared with that induced by TNF-α alone. Site-directed mutagenesis of a putative PPRE site in the sPLA 2 -IIA promoter abolished the potentiating effect of PPARα agonists, thus strongly indicating its contribution to the enhanced promoter activity. In summary, this study shows that the rat sPLA 2 -IIA promoter is sensitive to PPARα agonists, which act synergistically with cytokines, resulting in an enhanced expression of sPLA 2 -IIA in rat mesangial cells.

journal of the american society of nephrology

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