Inhibition of microRNA-429 in the renal medulla increased salt sensitivity of blood pressure in Sprague Dawley rats.
Inhibition of microRNA-429 in the renal medulla increased salt sensitivity of blood pressure in Sprague Dawley rats.
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DOI：
10.1097/hjh.0000000000001373
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发表时间：
2017-09
影响因子：
4.9
通讯作者：
Li N
中科院分区：
文献类型：
--
作者：
Zhu Q;Hu J;Wang L;Wang W;Wang Z;Li PL;Boini KM;Li N
我们之前已经证明，高盐摄入抑制脯氨酰羟化酶结构域蛋白2（PHD 2）的表达，这是一种促进缺氧诱导因子（HIF）-1α降解的酶，并增加HIF-1α沿着其在肾髓质中的靶基因，从而促进钠排泄并调节血压的盐敏感性。然而，尚不清楚高盐如何抑制PHD 2的表达。目前的研究首次揭示了高盐诱导的PHD 2抑制是由于mRNA的增强衰减。我们随后发现，高盐显著增加了肾脏髓质中miR-429的表达，随后证明其靶向PHD 2的3′-非翻译区并降低PHD 2水平。为了确定肾髓质miR-429在调节PHD 2/HIF-1α介导的肾脏对高盐摄入和血压盐敏感性的适应中的功能作用，我们在单侧肾切除大鼠中通过LNA anti-miR-429局部抑制肾髓质中的miR-429。我们的研究结果表明，抑制miR-429显著增加了PHD 2的水平，这破坏了PHD 2相关的HIF-1α介导的基因表达的适应性激活，从而抑制了尿钠排泄，增强了慢性钠超载的钠潴留，结果产生了盐敏感性高血压。结论：miR-429是PHD 2/HIF-1α相关肾脏适应高盐摄入的重要上游介质，肾脏髓质中miR-429介导的PHD 2抑制反应对高盐的缺乏可能代表盐敏感性高血压的致病机制。
We have previously shown that high salt intake suppresses the expression of prolyl hydroxylase domain-containing protein 2 (PHD2), an enzyme promoting the degradation of hypoxia inducible factor (HIF)-1α, and increases HIF-1α along with its target genes in the renal medulla, which promotes sodium excretion and regulate salt sensitivity of blood pressure. However, it remains unknown how high salt inhibits the expression of PHD2. The current study first revealed that high salt-induced PHD2 inhibition was due to the enhanced decay of mRNA. We then found that high salt significantly increased the expression of miR-429, which was subsequently proven to target the 3′-untranslated region of PHD2 and reduce PHD2 levels, in the renal medulla. To define the functional role of renal medullary miR-429 in the regulation of PHD2/HIF-1α-mediated renal adaptation to high salt intake and salt sensitivity of blood pressure, we locally inhibited miR-429 in the renal medulla by LNA anti-miR-429 in uninephrectomized rats. Our results demonstrated that inhibition of miR-429 remarkably increased the levels of PHD2, which disrupted PHD2-associated adaptive activation of HIF-1α-mediated gene expression in response to high salt in the renal medulla, and consequently inhibited urinary sodium excretion, enhanced sodium retention in response to chronic sodium overloading, and as a result, produced a salt-sensitive hypertension. It is concluded that miR-429 is an important upstream mediator in PHD2/HIF-1α-associated renal adaptation to high salt intake and that deficiency in miR-429-mediated PHD2 inhibition in response to high salt in the renal medulla may represent a pathogenic mechanism for salt-sensitive hypertension.