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

Abstract

Natural activators of peroxisome proliferator-activated receptors (PPAR) are lipid metabolites, including those produced by phospholipases A2 (PLA2). In glomerular mesagial 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 PPARα activators have an effect on sPLA2-IIA mRNA expression in rat mesangial cells, thus constituting a feedback modulation of sPLA2IIA 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 sPLA2 in mesangial cells. MK886, known as a noncompetitive inhibitor of PPARα, completely abolished the potentiation of sPLA2IIA 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 sPLA2-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 sPLA2-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 sPLA2-IIA promoter is sensitive to PPARα agonists, which act synergistically with cytokines, resulting in an enhanced expression of sPLA2-IIA in rat mesangial cells.