DYSREGULATION OF MICRORNA-181A CAUSED BY OVERACTIVE RENAL SYMPATHETIC NERVES CONTRIBUTES TO ELEVATED RENAL RENIN MRNA AND HYPERTENSION IN SCHLAGER BPH/2J MICE

Kristy Jackson, Cindy Gueguen, K Lim, Nina Eikelis, Fadi Joseph Charchar, Gavin W Lambert, Pamela J Davern, Francine Z. Marques, Geoffrey Head

Research output: Contribution to conferenceAbstract

Abstract

Objective: BPH/2J mice are a genetic model of hypertension driven by greater activity of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). BPH/2J mice display high levels of renal renin mRNA accompanied by low levels of its negative regulator microRNA-181a (miR181a), which is akin to that observed in hypertensive patients. Since miR181a levels also tended to correlate with the depressor response to ganglion blockade, we hypothesise that high renal sympathetic activity reduces miR181a levels, ultimately contributing to the augmented activity of the RAS in BPH/2J mice.
Design and method: To determine whether administering an in vivo miR-181a mimic or renal denervation can increase renal miR-181a abundance to reduce renal renin mRNA, RAS activity and hypertension in BPH/2J mice. Blood pressure (BP) in BPH/2J and normotensive BPN/3J mice was measured via pre-implanted radiotelemetry probes. One group were administered miR-181a mimic or a negative control (25nmol, n = 6–10) using an in vivo kidney specific transfection reagent and BP measured for 24hrs. Another group underwent renal denervation or sham surgery (n = 7–12) and BP measured for 3 weeks. Following these interventions, the BP response to ACE inhibition (enalaprilat) was determined and renal miR181a and renin mRNA abundance measured.
Results: Mir181a levels were greater in denervated BPH-2J mice compared with sham (P < 0.015). Furthermore renal renin mRNA abundance was lower in denervated (P < 0.05) and mimic treated BPH/2J mice (P < 0.001) compared with their respective controls. BP was reduced more after denervation than sham surgery in BPH/2J (P < 0.001) but not BPN/3J mice (P = 0.51). There was a peak hypotensive effect of the mimic 12–15hrs after injection in BPH/2J mice (−5.3 ± 1.4mmHg, P < 0.001) which was not present in negative control treated BPH/2J mice (P = 0.25) or in mimic or negative control treated BPN/3J mice (P > 0.15). The depressor response to enalaprilat was enhanced in denervated BPH/2J compared with sham (P < 0.003), whereas it was abolished in mimic treated BPH/2J mice compared with negative control (P < 0.001).
Conclusions: Taken together these findings provide the first in vivo evidence that elevated RSNA reduces miR-181a levels, which can contribute to greater renal renin mRNA level and hypertension in BPH/2J mice.
Original languageEnglish
Pagese41-e41
Number of pages1
DOIs
Publication statusPublished - Sep 2017

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