Signatures of miR-181a on the Renal Transcriptome and Blood Pressure

Abstract

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. Online address: http://www.molmed.org doi: 10.2119/molmed.2015.00096 Address correspondence to Maciej Tomaszewski, Institute of CardiovascularSciences, AV Hill Building, Dover Street, Manchester, M13 9PT, United Kingdom. Phone: +44-(0)116-275-0232; E-mail: maciej.tomaszewski@manchester.ac.uk. Submitted April 29, 2015; Accepted for publication August 17, 2015; Published Online (www.molmed.org ) August 24, 2015 m i R -1 8 1 a , T H E K I D N E Y A N D B L O O D P R E S S U R E7 4 0 | M a r q u E s E T a L . | M O L M E D 2 1 : 7 3 9 -7 4 8 , 2 0 1 5

The transcardiac gradient of cardio‐microRNAs in the failing heart

“…Moreover, we have previously found that miR‐181a was differentially expressed in human and mouse hypertensive kidneys . Consistent with the present study, we have also shown recently that circulating miR‐181a was associated with higher systolic and diastolic BP, through regulation of renin and pathways associated with the immune system and inflammation, consistent with immune system activation in heart failure . The circulating miRNA miR‐30e‐5p is down‐regulated in patients with acute heart failure .…”

Circulating microRNAs and hypertension—from new insights into blood pressure regulation to biomarkers of cardiovascular risk

“…More recently, we demonstrated that in two independent cohorts, serum levels of miR-181a correlated with systolic blood pressure. [16] Interestingly however, this association was opposite to that expected -increased miR-181a levels were associated with elevated blood pressure. Furthermore, this association was independent of circulating renin levels, suggesting that the effects of miR-181a may be mediated by mechanisms other than renin inhibition.…”

“…In an illustration of this, our group utilised circulating miR-181a to gain a deeper understanding of its association with blood pressure. [16] In 2011, Marques et al…”

“…This analysis implicated miR-181a in pathways associated with mitochondrial respiratory function, immunity and inflammation. [16] In a similar approach, the Vardas laboratory focussed on microRNAs linked to vascular smooth muscle modulation, [18] hypertrophy and endothelial dysfunction [19] in animal and tissue models.…”

Dual microRNA Screens Reveal That the Immune-Responsive miR-181 Promotes Henipavirus Entry and Cell-Cell Fusion

“…IL-1β, IL-6, and TNF-α) in blood tissues of humans with chronic inflammation, as well as blood of LPS-treated mice [46]. Additionally, miR-181 expression in human kidney tissues were found to be associated with increased transcription of genes of inflammation pathways [47]. As the biological relevance of miRNAs is linked to their prevalence [48], we considered examining changes in levels of miR-181 molecules in in vivo infection models for henipaviruses.…”