Rezaei Mina, Andrieu Thomas, Neuenschwander Samuel, Bruggmann Rémy, Mordasini David, Frey Felix J, Vogt Bruno, Frey Brigitte M
From the Department of Nephrology, Hypertension, and Clinical Pharmacology (M.R., T.A., D.M., F.J.F., B.V., B.M.F.) and Department of Biology and Bioinformatics (S.N., R.B.), University of Bern, Bern, Switzerland; Vital-IT, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland (S.N.); and Department of Clinical Research, University Hospital Bern, Bern, Switzerland (B.M.F.).
From the Department of Nephrology, Hypertension, and Clinical Pharmacology (M.R., T.A., D.M., F.J.F., B.V., B.M.F.) and Department of Biology and Bioinformatics (S.N., R.B.), University of Bern, Bern, Switzerland; Vital-IT, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland (S.N.); and Department of Clinical Research, University Hospital Bern, Bern, Switzerland (B.M.F.)
Hypertension. 2014 Oct;64(4):860-6. doi: 10.1161/HYPERTENSIONAHA.114.00002. Epub 2014 Jun 30.
The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is selectively expressed in aldosterone target tissues, conferring aldosterone selectivity for the mineralocorticoid receptor. A diminished activity causes salt-sensitive hypertension. The mechanism of the variable and distinct 11β-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) expression in the cortical collecting duct is poorly understood. Here, we analyzed for the first time whether the 11β-HSD2 expression is modulated by microRNAs (miRNAs). In silico analysis revealed 53 and 27 miRNAs with potential binding sites on human or rat HSD11B2 3'-untranslated region. A reporter assay demonstrated 3'-untranslated region-dependent regulation of human and rodent HSD11B2. miRNAs were profiled from cortical collecting ducts and proximal convoluted tubules. Bioinformatic analyses showed a distinct clustering for cortical collecting ducts and proximal convoluted tubules with 53 of 375 miRNAs, where 13 were predicted to bind to the rat HSD11B2 3'-untranslated region. To gain insight into potentially relevant miRNAs in vivo, we investigated 2 models with differential 11β-HSD2 activity linked with salt-sensitive hypertension. (1) Comparing Sprague-Dawley with low and Wistar rats with high 11β-HSD2 activity revealed rno-miR-20a-5p, rno-miR-19b-3p, and rno-miR-190a-5p to be differentially expressed. (2) Uninephrectomy lowered 11β-HSD2 activity in the residual kidney with differentially expressed rno-miR-19b-3p, rno-miR-29b-3p, and rno-miR-26-5p. In conclusion, miRNA-dependent mechanisms seem to modulate 11β-HSD2 dosage in health and disease states.
2型11β-羟类固醇脱氢酶（11β-HSD2）在醛固酮靶组织中选择性表达，赋予盐皮质激素受体对醛固酮的选择性。其活性降低会导致盐敏感性高血压。皮质集合管中2型11β-羟类固醇脱氢酶基因（HSD11B2）表达多变且独特的机制尚不清楚。在此，我们首次分析了11β-HSD2表达是否受微小RNA（miRNA）调控。计算机分析显示，有53个和27个miRNA在人或大鼠HSD11B2的3'非翻译区有潜在结合位点。报告基因检测证明了人及啮齿动物HSD11B2的3'非翻译区依赖性调控。对皮质集合管和近端曲管中的miRNA进行了分析。生物信息学分析显示，375个miRNA中的53个在皮质集合管和近端曲管中有明显聚类，其中13个被预测可与大鼠HSD11B2的3'非翻译区结合。为深入了解体内潜在相关的miRNA，我们研究了2个与盐敏感性高血压相关的、11β-HSD2活性不同的模型。（1）比较11β-HSD2活性低的Sprague-Dawley大鼠和活性高的Wistar大鼠，发现rno-miR-20a-5p、rno-miR-19b-3p和rno-miR-190a-5p表达存在差异。（2）单侧肾切除降低了残余肾中的11β-HSD2活性，rno-miR-19b-3p、rno-miR-29b-3p和rno-miR-26-5p表达存在差异。总之，miRNA依赖机制似乎在健康和疾病状态下调节11β-HSD2的剂量。
