PPARalpha activation upregulates nephrin expression in human embryonic kidney epithelial cells and podocytes by a dual mechanism.
Nephrin is an important member of the glomerular ultrafiltration complex and changes in its expression are associated with severe proteinuria. In this study, we show that synthetic PPARalpha agonists, but not PPARgamma agonists, stimulate an increased nephrin mRNA and protein expression in cultures of human podocytes and A293 human embryonic kidney epithelial cells which are blocked by the PPARalpha antagonist Ru486. Furthermore, the PPARalpha agonists have an additive effect on the interleukin-1beta (IL-1beta)-induced nephrin upregulation. Luciferase-reporter assays reveal that human nephrin promoter activity is stimulated by the PPARalpha agonists. Neither IL-1beta nor TNFalpha alone has an effect on nephrin promoter activity suggesting that additional posttranscriptional regulatory events might be operative. The role of nephrin mRNA stability regulation was evaluated in cells treated with actinomycin D to stop further RNA transcription. In the presence of PPARalpha agonists, IL-1beta or TNFalpha, the decay of nephrin mRNA was drastically reduced thus arguing for an additional posttranscriptional mode of action. In summary, these data show that PPARalpha activation causes an increased nephrin expression by a dual action, on the one hand by stimulating nephrin promoter activity and on the other hand by reducing nephrin mRNA degradation. These findings may have importance for treatment strategies of renal diseases affecting the expression of nephrin and subsequently the proper action of the glomerular filtration apparatus.
Ren
Shuyu
S
Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Xin
Cuiyan
C
Beck
Karl-Friedrich
KF
Saleem
Moin A
MA
Mathieson
Peter
P
Pavenstädt
Hermann
H
Pfeilschifter
Josef
J
Huwiler
Andrea
A
D001629:Bezafibrate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D015735:Mifepristone / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
D007375:Interleukin-1; D008565:Membrane Proteins; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C113267:nephrin; D015735:Mifepristone; C006253:pirinixic acid; D001629:Bezafibrate