Hypoxia-inducible factor prolyl-hydroxylase 2 senses high-salt intake to increase hypoxia inducible factor 1alpha levels in the renal medulla.
Hypoxia-inducible factor prolyl-hydroxylase 2 senses high-salt intake to increase hypoxia inducible factor 1alpha levels in the renal medulla.
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DOI：
10.1161/hypertensionaha.109.145896
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发表时间：
2010-05
期刊：
影响因子：
--
通讯作者：
Li N
中科院分区：
文献类型：
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作者：
Wang Z;Zhu Q;Xia M;Li PL;Hinton SJ;Li N
高盐可诱导转录因子缺氧诱导因子（HIF）-1α及其靶基因在肾髓质的表达，这是肾脏对高盐摄入的重要适应机制。含HIF脯氨酰羟化酶结构域的蛋白（PHDs）是促进HIF-1α降解的主要酶。PHD 2是肾脏中PHD的主要同种型，并且主要在肾髓质中表达。本研究验证了PHD 2对高盐反应并介导高盐诱导的肾髓质中HIF-1α水平升高的假设。在正常血压大鼠，高盐摄入（4%NaCl，10天）显着抑制PHD 2的表达和酶活性在肾髓质。PHD 2转基因肾髓质过表达显著降低HIF-1α水平。PHD 2转基因还阻断了高盐诱导的肾髓质中HIF-1α靶基因血红素加氧酶-1和一氧化氮合酶-2的激活。然而，在Dahl盐敏感性高血压大鼠中，高盐摄入并没有抑制肾髓质中PHD 2的表达和活性。相应地，在这些大鼠中，肾髓质HIF-1α水平没有被高盐摄入上调。转染PHD 2 shRNA后，高盐摄入可显著上调Dahl S大鼠HIF-1α及其靶基因表达。PHD 2转基因在肾髓质中的过表达损害盐负荷后的肾钠排泄。这些数据表明，高盐摄入抑制肾髓质中的PHD 2，从而上调HIF-1α表达。PHD介导的高盐反应的缺乏可能代表了盐敏感性高血压的发病机制。
High salt induces the expression of transcription factor hypoxia-inducible factor (HIF)-1α and its target genes in the renal medulla, which is an important renal adaptive mechanism to high salt intake. HIF prolyl hydroxylase domain-containing proteins (PHDs) have been identified as major enzymes to promote the degradation of HIF-1α. PHD2 is the predominant isoform of PHDs in the kidney and primarily expressed in the renal medulla. The present study tested the hypothesis that PHD2 responds to high salt and mediates high salt-induced increase in HIF-1α levels in the renal medulla. In normotensive rats, high salt intake (4% NaCl, 10 days) significantly inhibited PHD2 expressions and enzyme activities in the renal medulla. Renal medullary overexpression of PHD2 transgene significantly decreased HIF-1α levels. PHD2 transgene also blocked high salt-induced activation of HIF-1α target genes heme oxygenase-1 and nitric oxide synthase-2 in the renal medulla. In Dahl salt-sensitive hypertensive rats, however, high salt intake did not inhibit the expression and activities of PHD2 in the renal medulla. Correspondingly, renal medullary HIF-1α levels were not up-regulated by high salt intake in these rats. After transfection of PHD2 shRNA, HIF-1α and its target genes were significantly up-regulated by high salt intake in Dahl S rats. Overexpression of PHD2 transgene in the renal medulla impaired renal sodium excretion after salt loading. These data suggest that high salt intake inhibits PHD2 in the renal medulla, thereby upregulating the HIF-1α expression. The lack of PHD-mediated response to high salt may represent a pathogenic mechanism producing salt sensitive hypertension.