Potentiation of TNF-α-stimulated group IIA phospholipase A2 expression by peroxisome proliferator-activated receptor α activators in rat mesangial cells

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 PPARalpha activators have an effect on sPLA(2)-IIA rnRNA expression in rat mesangial cells, thus constituting a feedback modulation of sPLA(2)-IIA transcription. In the presence of tumor necrosis factor-alpha (TNF-alpha), the PPARalpha 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 PPARalpha, completely abolished the potentiation of sPLA(2)-IIA secretion and activity by WY14643, thus indicating that the effect of WY14643 is specifically mediated by PPARalpha. When cells were transfected with different constructs of the rat sPLA(2)-IIA promoter fused to a luciferase reporter gene, a stimulation with TNF-alpha in the presence of the PPARalpha activators caused an enhanced promoter activity compared with that induced by TNF-alpha alone. Site-directed mutagenesis of a putative PPRE site in the sPLA(2)-IIA promoter abolished the potentiating effect of PPARalpha 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 PPARalpha agonists, which act synergistically with cytokines, resulting in an enhanced expression of sPLA(2)-IIA in rat mesangial cells.