Marques Francine Z, Romaine Simon Pr, Denniff Matthew, Eales James, Dormer John, Garrelds Ingrid M, Wojnar Lukasz, Musialik Katarzyna, Duda-Raszewska Barbara, Kiszka Bartlomiej, Duda Magdalena, Morris Brian J, Samani Nilesh J, Danser Ah Jan, Bogdanski Pawel, Zukowska-Szczechowska Ewa, Charchar Fadi J, Tomaszewski Maciej
Faculty of Science and Technology, School of Applied and Biomedical Sciences, Federation University Australia, Victoria, Australia.
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
Mol Med. 2015 Nov;21(1):739-748. doi: 10.2119/molmed.2015.00096. Epub 2015 Aug 24.
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 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.
微小RNA - 181a与肾素信使核糖核酸（mRNA）的3'非翻译区结合，肾素是肾素 - 血管紧张素系统的一种限速酶。我们的目标是确定这种分子相互作用是否转化为对血压具有临床意义的影响，以及循环中的微小RNA - 181a是否是血压的可测量替代指标。在“人类肾脏转录组（TRANSLATE）研究”的200个肾脏中，肾脏微小RNA - 181a是肾素mRNA的唯一负向预测因子，并且与循环中的微小RNA - 181a密切相关。在TRANSLATE研究中，微小RNA - 181a水平升高与收缩压和舒张压呈正相关，且这种关联独立于循环肾素。来自“社区人群动脉血压的遗传调控（GRAPHIC）研究”的199名受试者重复了血清微小RNA - 181a与收缩压之间的关联。肾脏免疫组织化学和杂交显示，微小RNA - 181a与肾素的共定位在肾素不释放到体循环的集合管中最为显著。对69个通过RNA测序表征的人类肾脏进行分析发现，微小RNA - 181a与四个线粒体途径的下调以及适应性免疫和炎症的41个信号级联的上调相关。我们得出结论，肾脏微小RNA - 181a对与血压调节相关的途径具有多效性作用，并且微小RNA - 181a的循环水平既是肾脏微小RNA - 181a表达的可测量替代指标，也是血压的一种新型生化关联指标。
