Neural suppression of miRNA-181a in the kidney elevates renin expression and exacerbates hypertension in Schlager mice
- Authors: Jackson, Kristy , Gueguen, Cindy , Lim, Kyungjoon , Eikelis, Nina , Stevenson, Emily , Charchar, Fadi , Lambert, Gavin , Burke, Sandra , Paterson, Madeleine , Marques, Francine , Head, Geoffrey
- Date: 2020
- Type: Text , Journal article
- Relation: Hypertension Research Vol. 43, no. 11 (2020), p. 1152-1164
- Full Text: false
- Reviewed:
- Description: 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. © 2020, The Japanese Society of Hypertension.
- Description: 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).
Renal nerves contribute to hypertension in Schlager BPH/2J mice
- Authors: Gueguen, Cindy , Jackson, Kristy , Marques, Francine , Eikelis, Nina , Phillips, Sarah , Stevenson, Emily , Charchar, Fadi , Lambert, Gavin , Davern, Pamela , Head, Geoffrey
- Date: 2019
- Type: Text , Journal article
- Relation: Hypertension Research Vol. 42, no. 3 (2019), p. 306-318
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- Description: Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J. Mean arterial pressure (MAP) was measured by radiotelemetry before and for 3 weeks after RD in BPH/2J and BPN/3J. The effects of pentolinium and enalaprilat were examined to determine the contribution of the SNS and RAS, respectively. After 3 weeks, MAP was −10.9 ± 2.1 mmHg lower in RD BPH/2J compared to baseline and −2.1 ± 2.2 mmHg in sham BPH/2J (P < 0.001, n = 8–10). RD had no effect in BPN/3J (P > 0.1). The depressor response to pentolinium was greater in BPH/2J than BPN/3J, but in both cases the response in RD mice was similar to sham. Enalaprilat decreased MAP more in RD BPH/2J compared to sham (−12 vs −3 mmHg, P < 0.001) but had no effect in BPN/3J. RD reduced renal noradrenaline in both strains but more so in BPH/2J. RD reduced renin mRNA and protein, but not plasma renin in BPH/2J to levels comparable with BPN/3J mice. We conclude that renal nerves contribute to hypertension in BPH mice as RD induced a sustained fall in MAP, which was associated with a reduction of intrarenal renin expression. The lack of inhibition of the depressor effects of pentolinium and enalaprilat by RD suggests that vasoconstrictor effects of the SNS or RAS are not involved.
The emerging role of non-coding RNA in essential hypertension and blood pressure regulation
- Authors: Marques, Francine , Booth, Scott , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Human Hypertension Vol. 29, no. 8 (2015), p. 459-467
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: Unravelling the complete genetic predisposition to high blood pressure (BP) has proven to be challenging. This puzzle and the fact that coding regions of the genome account for less than 2% of the entire human DNA support the hypothesis that genetic mechanism besides coding genes are likely to contribute to BP regulation. Non-coding RNAs (ncRNAs) are emerging as key players of transcription regulation in both health and disease states. They control basic functions in virtually all cell types relevant to the cardiovascular system and, thus, a direct involvement with BP regulation is highly probable. Here, we review the literature about ncRNAs associated with human BP and essential hypertension, highlighting investigations, methodology and difficulties arising in the field. The most investigated ncRNAs so far are microRNAs (miRNAs), small ncRNAs that modulate gene expression by posttranscriptional mechanisms. We discuss studies that have examined miRNAs associated with BP in biological fluids, such as blood and urine, and tissues, such as vascular smooth muscle cells and the kidney. Furthermore, we review the interaction between miRNA binding sites and single nucleotide polymorphisms in genes associated with BP. In conclusion, there is a clear need for more human and functional studies to help elucidate the multifaceted roles of ncRNAs, in particular mid- and long ncRNAs in BP regulation. © 2015 Macmillan Publishers Limited All rights reserved.
A novel interaction between sympathetic overactivity and aberrant regulation of renin by miR-181a in BPH/2J genetically hypertensive mice
- Authors: Jackson, Kristy , Marques, Francine , Watson, Anna , Palma-Rigo, Keisia , Nguyen-Huu, Thu-Phuc , Morris, Brian , Charchar, Fadi , Davern, Pamela , Head, Geoffrey
- Date: 2013
- Type: Text , Journal article
- Relation: Hypertension Vol. 62 , no. 4 (2013), p. 775-781
- Full Text: false
- Reviewed:
- Description: Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg i.p.) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg i.p.) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin-angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin-angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.