Signatures of miR-181a on the Renal Transcriptome and Blood Pressure
Signatures of miR-181a on the Renal Transcriptome and Blood Pressure
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DOI：
10.2119/molmed.2015.00096
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发表时间：
2015-08
影响因子：
5.7
通讯作者：
F. Marques;Siôn Romaine;M. Denniff;James M. Eales;J. Dormer;I. Garrelds;L. Wojnar;K. Musialik;Barbara Duda-Raszewska;Bartłomiej Kiszka;M. Duda;B. Morris;N. Samani;A. Danser;P. Bogdański;E. Zukowska-szczechowska;F. Charchar;M. Tomaszewski
中科院分区：
文献类型：
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作者：
F. Marques;Siôn Romaine;M. Denniff;James M. Eales;J. Dormer;I. Garrelds;L. Wojnar;K. Musialik;Barbara Duda-Raszewska;Bartłomiej Kiszka;M. Duda;B. Morris;N. Samani;A. Danser;P. Bogdański;E. Zukowska-szczechowska;F. Charchar;M. Tomaszewski
microRNA-181 a与肾素信使RNA（mRNA）的3′非翻译区结合，肾素是肾素-血管紧张素系统的限速酶。我们的目的是确定这种分子相互作用是否转化为对血压的临床意义的影响，以及循环miR-181 a是否是血压的可测量代表。在来自肾组织转录组（TRANSLATE）研究的200个人肾脏中，肾脏miR-181 a是肾素mRNA的唯一阴性预测因子，与循环miR-181 a密切相关。在TRANSLATE中，miR-181 a水平升高与收缩压和舒张压呈正相关，这种相关性不依赖于循环肾素。血清miR-181 a和收缩压之间的关联在来自社区人类动脉压遗传调节（GRAPHIC）研究的199名受试者中复制。肾脏免疫组织化学和原位杂交显示，miR-181 a和肾素的共定位在集合管中最突出，其中肾素不释放到体循环中。对69个通过RNA测序表征的人类肾脏的分析显示，miR-181 a与4个线粒体途径的下调和41个适应性免疫和炎症信号级联的上调相关。我们得出结论，肾脏miR-181 a对血压调节相关通路具有多效性作用，并且循环miR-181 a水平既是肾脏miR-181 a表达的可测量代表，也是血压的新生化相关性。
MicroRNA-181a binds to the 3′ untranslated region of messenger RNA (mRNA) for renin, a rate-limiting enzyme of the renin-angiotensin system. Our objective was to determine whether this molecular interaction translates into a clinically meaningful effect on blood pressure and whether circulating miR-181a is a measurable proxy of blood pressure. In 200 human kidneys from the TRANScriptome of renaL humAn TissuE (TRANSLATE) study, renal miR-181a was the sole negative predictor of renin mRNA and a strong correlate of circulating miR-181a. Elevated miR-181a levels correlated positively with systolic and diastolic blood pressure in TRANSLATE, and this association was independent of circulating renin. The association between serum miR-181a and systolic blood pressure was replicated in 199 subjects from the Genetic Regulation of Arterial Pressure of Humans In the Community (GRAPHIC) study. Renal immunohistochemistry and in situ hybridization showed that colocalization of miR-181a and renin was most prominent in collecting ducts where renin is not released into the systemic circulation. Analysis of 69 human kidneys characterized by RNA sequencing revealed that miR-181a was associated with downregulation of four mitochondrial pathways and upregulation of 41 signaling cascades of adaptive immunity and inflammation. We conclude that renal miR-181a has pleiotropic effects on pathways relevant to blood pressure regulation and that circulating levels of miR-181a are both a measurable proxy of renal miR-181a expression and a novel biochemical correlate of blood pressure.