Aldosterone-induced microRNAs act as feedback regulators of mineralocorticoid receptor signaling in kidney epithelia.
Aldosterone-induced microRNAs act as feedback regulators of mineralocorticoid receptor signaling in kidney epithelia.
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DOI：
10.1096/fj.201902254rr
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发表时间：
2020-09
期刊：
影响因子：
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通讯作者：
Butterworth MB
中科院分区：
文献类型：
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作者：
Ozbaki-Yagan N;Liu X;Bodnar AJ;Ho J;Butterworth MB
肾素 - 血管紧张素 - 醛固酮信号系统（RAAS）的最后步骤涉及皮质类固醇激素醛固酮与其盐皮质激素受体（MR）的结合。结合后的MR与反应元件相互作用，以诱导或抑制醛固酮调节基因的转录。一个特征明确的醛固酮诱导基因是血清和糖皮质激素诱导激酶（SGK1），它在下游发挥作用，增加远端肾单位上皮细胞的钠转运。长期醛固酮刺激诱导的微小RNA（miRs）在调节MR和SGK1中的作用尚未见报道。在这些研究中，通过qRT - PCR对醛固酮刺激后预测能与小鼠MR的3’ - 非翻译区（3’ - UTR）结合的miRs进行了分析。miR - 466a/b/c/e家族在小鼠肾皮质集合管上皮细胞中表达上调。荧光素酶报告基因检测证实miR - 466与MR和SGK1的3’ - UTR均能结合。抑制miR - 466可使MR和SGK1的mRNA及蛋白水平升高。抑制miR - 466b并阻止其在醛固酮刺激后上调，可增加阿米洛利敏感的钠转运以及对醛固酮刺激的敏感性。在低钠饮食小鼠的远端肾单位中证实了miR - 466在体内的上调。醛固酮诱导的miRs对MR和SGK1的抑制可能代表一种负反馈回路，这有助于体内某种形式的醛固酮逃逸。
The final steps in the Renin-Angiotensin-Aldosterone signaling System (RAAS) involve binding of the corticosteroid hormone, aldosterone to its mineralocorticoid receptor (MR). The bound MR interacts with response elements to induce or repress the transcription of aldosterone-regulated genes. A well characterized aldosterone-induced gene is the serum and glucocorticoid induced kinase (SGK1) which acts downstream to increase sodium transport in distal kidney nephron epithelial cells. The role of microRNAs (miRs) induced by extended aldosterone stimulation in regulating MR and SGK1 has not been reported. In these studies, miRs predicted to bind to the 3’-UTR of mouse MR were profiled by qRT-PCR after aldosterone stimulation. The miR-466a/b/c/e family was upregulated in mouse kidney cortical collecting duct epithelial cells. A luciferase reporter assay confirmed miR-466 binding to both MR and SGK1 3’-UTRs. Inhibition of miR-466 increased MR and SGK1 mRNA and protein levels. Inhibiting miR-466b and preventing its upregulation after aldosterone stimulation increased amiloride-sensitive sodium transport and sensitivity to aldosterone stimulation. In vivo up-regulation of miR-466 was confirmed in distal nephrons of mice on low Na+ diets. Repression of MR and SGK1 by aldosterone-induced miRs may represent a negative feedback loop that contributes to a form of aldosterone escape in vivo.