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 PPAR alpha agonists, but not PPAR gamma 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 PPAR alpha antagonist RU486. Furthermore, the PPARa agonists have an additive effect on the interleukin-1 beta (IL-1 beta)-induced nephrin upregulation. Luciferase-reporter assays reveal that human nephrin promoter activity is stimulated by the PPAR alpha agonists. Neither IL-1 beta nor TNF alpha 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 PPAR alpha agonists, IL-1 beta or TNF alpha, the decay of nephrin mRNA was drastically reduced thus arguing for an additional posttranscriptional mode of action. In summary, these data show that PPAR alpha 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. (c) 2005 Elsevier Inc. All rights reserved.