Potentiation of TNF-alpha-stimulated group IIA phospholipase A(2) expression by peroxisome proliferator-activated receptor alpha 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 PPAR(alpha) 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-alpha (TNF-alpha), the PPAR(alpha) 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 PPAR(alpha), completely abolished the potentiation of sPLA(2)-IIA secretion and activity by WY14643, thus indicating that the effect of WY14643 is specifically mediated by PPAR(alpha). 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 PPAR(alpha) 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 PPAR(alpha) 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 PPAR(alpha) agonists, which act synergistically with cytokines, resulting in an enhanced expression of sPLA(2)-IIA in rat mesangial cells.
Scholz-Pedretti
Kirsten
K
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Gans
Annette
A
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Beck
Karl-Friedrich
KF
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Pfeilschifter
Josef
J
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Kaszkin
Marietta
M
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D004357:Drug Synergism; D017353:Gene Deletion; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D054501:Group II Phospholipases A2; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D010741:Phospholipases A / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D002722:Chlorobenzenes
D000098:Acetophenones; D054501:Group II Phospholipases A2; D007211:Indoles; D020025:Peroxisome Proliferators; D010741:Phospholipases A; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013777:Tetrazoles; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C060893:MK-886; D002722:Chlorobenzenes; C006253:pirinixic acid; C044660:LY 171883