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This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2004121051v1 16/10/2897    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petry, C. Articles by Pfeilschifter, J. Search for Related Content PubMed PubMed Citation Articles by Petry, C. Articles by Pfeilschifter, J. Related Collections Related Article

Hypoxia Increases Group IIA Phospholipase A₂ Expression under Inflammatory Conditions in Rat Renal Mesangial Cells

Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

Address correspondence to: Dr. Josef Pfeilschifter, Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. Phone: +49-69-6301-6951; Fax: +49-69-6301-7942; E-mail: pfeilschifter{at}em.uni-frankfurt.de

Received for publication December 7, 2004. Accepted for publication July 25, 2005.

Hypoxia evokes a common mechanism of oxygen sensing mediated by hypoxia-inducible transcription factors (HIF) in many mammalian cells. This study investigated the effect of hypoxia on group-IIA secretory phospholipase A₂ (sPLA₂-IIA) expression in renal mesangial cells. Stimulation of cells with IL-1 under normoxic conditions (21% O₂) is known to induce expression and secretion of the group sPLA₂-IIA. This induction is further enhanced by constantly reducing the O₂ concentration to 1% O₂, and is accompanied by increased sPLA₂ activity. To see whether hypoxia potentiates IL-1–induced sPLA₂-IIA gene expression, a 2.67-kb fragment of the rat sPLA₂-IIA promoter was fused to a luciferase reporter construct and used to transfect mesangial cells. Hypoxia alone is not able to activate the sPLA₂ promoter, whereas it significantly enhances IL-1–stimulated promoter activity. A deletion mutant of the promoter that lacks the two putative hypoxia responsive elements (HRE) is devoid of the potentiating effect of hypoxia. Moreover, site-directed mutagenesis of either of the two HRE is sufficient to abolish the potentiating effect of hypoxia. Electrophoretic mobility shift assays show that HIF-2, which is the only HIF subtype expressed in mesangial cells, binds to both HRE in the sPLA₂-IIA promoter. In summary, the data show that in an inflammatory setting hypoxia is able to potentiate sPLA₂-IIA expression and activity in renal mesangial cells, and thereby may critically contribute to enhanced formation of inflammatory lipid mediators seen in a diverse range of kidney diseases.

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