Signatures of miR-181a on the Renal Transcriptome and Blood Pressure
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.
We thank Boye Schnack Nielsen from Bioneer S/A (Denmark) for his help with the in situ hybridization and immunohistochemistry. This work was supported by grants from British Heart Foundation (PG/12/9/29376 to M Tomaszewski and J Eales), the National Health & Medical Research Council of Australia (NHMRC project grant 526662 to FJ Charchar) and the Federation University Australia Self-Sustaining Regions Research and Innovation Initiative, an Australian Government Collaborative Research Network grant (to FJ Charchar and FZ Marques). FZ Marques is supported by a NHMRC (APP1052659) and National Heart Foundation (PF12M6785) co-shared Early Career Fellowships. SPR Romaine is supported by Health Education East Midlands.
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