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Transcriptional Regulation of Nephrin Gene by Peroxisome Proliferator–Activated Receptor- Agonist: Molecular Mechanism of the Antiproteinuric Effect of Pioglitazone

Ariela Benigni^*, Carla Zoja^*, Susanna Tomasoni^*, Marco Campana^*, Daniela Corna^*, Cristina Zanchi^*, Elena Gagliardini^*, Elvira Garofano^*, Daniela Rottoli^*, Takahito Ito and Giuseppe Remuzzi^*,

^* Mario Negri Institute for Pharmacological Research and Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy; and Osaka University School of Medicine, Suita, Japan

Address correspondence to: Dr. Ariela Benigni, "Mario Negri" Institute for Pharmacological Research, Via Gavazzeni 11, Bergamo 24125, Italy. Phone: +39-035-319-888; Fax: +39-035-319-331; E-mail: abenigni{at}marionegri.it

Received for publication September 21, 2005. Accepted for publication April 7, 2006.

The renoprotective potential of the peroxisome proliferator–activated receptor- (PPAR-) agonist pioglitazone was explored in an immune model of progressive nephropathy, passive Heymann nephritis (PHN), compared with that of an angiotensin II receptor antagonist, taken as standard therapy for renoprotection. PHN rats received orally vehicle, pioglitazone (10 mg/kg twice daily), or candesartan (1 mg/kg twice daily) from months 2 to 8. Pioglitazone reduced proteinuria as effectively as candesartan and limited renal functional and structural changes. Kidneys from untreated PHN rats showed lower nephrin mRNA and protein than controls, both restored by pioglitazone. The effect was seen both early and late during the course of the disease. Whether the antiproteinuric effect of pioglitazone could be due to its effect on nephrin gene transcription also was investigated. HK-2 cells were transfected with plasmids that harbor the luciferase gene under portions (2-kb or 325-bp) of human nephrin gene promoter that contain putative peroxisome proliferator–responsive elements (PPRE) and incubated with pioglitazone (10 µM). Transcriptional activity of luciferase gene was highly increased by pioglitazone, with the strongest expression achieved with the 325-bp fragment. Increase in luciferase activity was prevented by bisphenol A diglycidyl ether, a PPAR- synthetic antagonist. Electrophoretic mobility shift assay experiments showed a direct interaction of PPAR/retinoid X receptor heterodimers to PPRE present in the enhancer region of the nephrin promoter. In conclusion, pioglitazone exerts an antiproteinuric effect in immune-mediated glomerulonephritis as angiotensin II receptor antagonist does. Enhancement of nephrin gene transcription through specific PPRE in its promoter discloses a novel mechanism of renoprotection for PPAR- agonists.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673