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首页> 外文期刊>Journal of the American Society of Nephrology: JASN >Hypoxia increases group IIA phospholipase A(2) expression under inflammatory conditions in rat renal mesangial cells.
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Hypoxia increases group IIA phospholipase A(2) expression under inflammatory conditions in rat renal mesangial cells.

机译：缺氧增加炎症性条件下大鼠肾系膜细胞中IIA组磷脂酶A（2）的表达。

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摘要

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 A(2) (sPLA(2)-IIA) expression in renal mesangial cells. Stimulation of cells with IL-1beta under normoxic conditions (21% O(2)) is known to induce expression and secretion of the group sPLA(2)-IIA. This induction is further enhanced by constantly reducing the O(2) concentration to 1% O(2), and is accompanied by increased sPLA(2) activity. To see whether hypoxia potentiates IL-1beta-induced sPLA(2)-IIA gene expression, a 2.67-kb fragment of the rat sPLA(2)-IIA promoter was fused to a luciferase reporter construct and used to transfect mesangial cells. Hypoxia alone is not able to activate the sPLA(2) promoter, whereas it significantly enhances IL-1beta-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-2alpha, which is the only HIF subtype expressed in mesangial cells, binds to both HRE in the sPLA(2)-IIA promoter. In summary, the data show that in an inflammatory setting hypoxia is able to potentiate sPLA(2)-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.
机译：缺氧引起了许多哺乳动物细胞中由缺氧诱导转录因子（HIF）介导的氧感测的常见机制。这项研究调查了缺氧对肾小球系膜细胞中IIA组分泌型磷脂酶A（2）（sPLA（2）-IIA）表达的影响。在常氧条件下（21％O（2））用IL-1beta刺激细胞可诱导sPLA（2）-IIA组的表达和分泌。通过不断降低O（2）浓度至1％O（2）来进一步增强这种诱导作用，并伴随增加sPLA（2）活性。若要查看缺氧是否增强了IL-1β诱导的sPLA（2）-IIA基因表达，将大鼠sPLA（2）-IIA启动子的2.67 kb片段与荧光素酶报道基因构建体融合，并用于转染肾小球膜细胞。单独的缺氧不能激活sPLA（2）启动子，而它可以显着增强IL-1beta刺激的启动子活性。缺少两个假定的缺氧反应元件（HRE）的启动子的缺失突变体缺乏缺氧的增强作用。此外，两个HRE之一的定点诱变足以消除缺氧的增强作用。电泳迁移率迁移分析表明，HIF-2alpha是系膜细胞中表达的唯一HIF亚型，与sPLA（2）-IIA启动子中的两个HRE结合。总之，数据表明，在炎症性环境中，低氧能够增强肾小球膜细胞中sPLA（2）-IIA的表达和活性，从而可能在多种肾脏疾病中均显着促进炎症脂质介质的形成。 。

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