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Neural suppression of miRNA-181a in the kidney elevates renin expression and exacerbates hypertension in Schlager mice

Hypertension Research volume 43, pages 1152–1164 (2020)Cite this article

Abstract

BPH/2J mice are a genetic model of hypertension with overactivity of the sympathetic nervous system (SNS) and renin–angiotensin system (RAS). BPH/2J display higher renal renin mRNA and low levels of its negative regulator microRNA-181a (miR-181a). We hypothesise that high renal SNS activity may reduce miR-181a expression, which contributes to elevated RAS activity and hypertension in BPH/2J. Our aim was to determine whether in vivo administration of a renal-specific miR-181a mimic or whether renal denervation could 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 radiotelemetry probes. Mice were administered miR-181a mimic or a negative control (1–25 nmol, i.v., n = 6–10) with BP measured for 48 h after each dose or they underwent renal denervation or sham surgery (n = 7–9). Injection of 5–25 nmol miR-181a mimic reduced BP in BPH/2J mice after 36–48 h (−5.3 ± 1.8, −6.1 ± 1.9 mmHg, respectively, P < 0.016). Treatment resulted in lower renal renin and inflammatory marker (TLR4) mRNA levels in BPH/2J. The mimic abolished the hypotensive effect of blocking the RAS with enalaprilat (P < 0.01). No differences between mimic or vehicle were observed in BPN/3J mice except for a higher level of renal angiotensinogen in the mimic-treated mice. Renal miR-181a levels that were lower in sham BPH/2J mice were greater following renal denervation and were thus similar to those of BPN/3J. Our findings suggest that the reduced renal miR-181a may partially contribute to the elevated BP in BPH/2J mice, through an interaction between the renal sympathetic nerves and miR-181a regulation of the RAS.

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Acknowledgements

We acknowledge the technical assistance of Thu-Phuc Nguyen-Huu and John-Luis Moretti. We thank Dr Anna Watson for kindly providing the TLR4, ACE, AT2 and CD36 Taqman mixes and Dr Christos Tikellis for the ACE2 and AT1aR Taqman mixes.

Funding

This work was supported by a grant from the National Health & Medical Research Council of Australia (NHMRC, Project grant 1065714) and in part by the Victorian Government’s OIS Program. Investigators were supported by NHMRC/National Heart Foundation (NHF) Postdoctoral Fellowships (NHMRC APP1091688 to KLJ, NHMRC APP1052659 and NHF PF12M6785 and 101185 to FZM) and NHMRC Research Fellowships (APP1042492 to GWL and APP1002186 to GAH).

Author information

Author notes

  1. These authors contributed equally: Kristy L. Jackson, Cindy Gueguen

  2. These authors jointly supervised this work: Francine Z. Marques, Geoffrey A. Head

Authors and Affiliations

  1. Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia

    Kristy L. Jackson, Cindy Gueguen, Kyungjoon Lim, Emily R. Stevenson, Sandra L. Burke & Geoffrey A. Head

  2. Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC, Australia

    Kyungjoon Lim

  3. Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia

    Nina Eikelis & Gavin W. Lambert

  4. Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, VIC, Australia

    Nina Eikelis & Gavin W. Lambert

  5. Faculty of Science and Technology, Federation University Australia, Ballarat, VIC, Australia

    Fadi J. Charchar & Francine Z. Marques

  6. Hypertension Research Laboratory, School of Biological Sciences, Monash University, Clayton, VIC, Australia

    Madeleine R. Paterson & Francine Z. Marques

  7. Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia

    Francine Z. Marques

  8. Department of Pharmacology, Monash University, Clayton, VIC, Australia

    Geoffrey A. Head

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  1. Kristy L. Jackson
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Contributions

KLJ, CG, KL, FZM, NE, ERS and MRP performed the study including experimental data collection, assays and analyses. CG, KLJ, KL, FZM, NE, ERS, FJC, GWL, SLB, MRP and GAH contributed to the analysis, writing and preparation of the manuscript.

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Correspondence to Geoffrey A. Head.

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Conflict of interest

GWL received research support from Medtronic and has acted as a consultant for Medtronic. GAH has received research support from Boehringer Ingelheim. Both are unrelated to the current study.

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Jackson, K.L., Gueguen, C., Lim, K. et al. Neural suppression of miRNA-181a in the kidney elevates renin expression and exacerbates hypertension in Schlager mice. Hypertens Res 43, 1152–1164 (2020). https://doi.org/10.1038/s41440-020-0453-x

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