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

Jackson, Kristy L.; Gueguen, Cindy; Lim, Kieran F.; Eikelis, Nina; Stevenson, Emily V.; Charchar, Fadi J.; Lambert, Gavin W.; Burke, Sandra L.; Paterson, Madeleine; Marques, Francine Z.; Head, Geoffrey A.

doi:10.1038/s41440-020-0453-x

Cited by 13 publications

(13 citation statements)

References 30 publications

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“…On the contrary, TH staining, a marker of sympathetic innervation, was greater in miR-181a/b-1 KO mice than wild-type mice, consistent with our scRNA-seq data. Combined with recent findings showing that renal denervation reduced BP and restored levels of miR-181a in the hypertensive mice, 36 this may imply that the SNS has a role, either directly or indirectly, in the regulation of miR-181a.…”

Section: Discussionmentioning

confidence: 55%

“…7 Indeed, renal denervation lowered BP and normalised expression of miR-181a and renin in Schlager hypertensive (BPH/2J) mice with neurogenic hypertension, but not in normotensive control mice. 36 Since BPH/2J mice and miR-181a/b-1 KO mice have lower miR-181a levels, one may expect to see altered sympathetic activity in the KO mice. 7 However, on a normal- salt diet, the depressor response to ganglionic blockade in miR-181a/b-1 KO mice was similar to that of WT mice, both in the active and inactive period.…”

Section: Discussionmentioning

confidence: 99%

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Deficiency of MicroRNA-181a Results in Transcriptome-Wide Cell Specific Changes in the Kidney that Lead to Elevated Blood Pressure and Salt Sensitivity

Paterson

Jackson

Donà³

et al. 2021

Preprint

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MicroRNA miR-181a is down-regulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a knockout mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radio-telemetry probes were implanted in twelve-week-old C57BL/6J wild-type and miR-181a/b-1 knockout mice. Systolic and diastolic BP were 4-5mmHg higher in knockout compared with wild-type mice over 24-hours (P<0.01). Compared with wild-type mice, renal renin was higher in the juxtaglomerular cells of knockout mice. BP was similar in wild-type mice on a high (3.1%) versus low (0.3%) sodium diet (+0.4±0.8mmHg) but knockout mice showed salt sensitivity (+3.3±0.8mmHg, P<0.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA-sequencing in 6,699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, Smad4. We observed up-regulation of pathways related to the immune system, inflammatory response, reactive oxygen species and nerve development, consistent with higher tyrosine hydroxylase. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Deficiency of MicroRNA-181a Results in Transcriptome-Wide Cell Specific Changes in the Kidney that Lead to Elevated Blood Pressure and Salt Sensitivity

Paterson

Jackson

Donà³

et al. 2021

Preprint

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“…In genetically hypertensive BPH/2J mice, overactivation of the sympathetic system also induces increased renin release through sympathetic hyperstimulation of the kidney, while miR-181a downregulation in this context is associated with increased renin synthesis [ 240 ]. miR-181a mimic injection reduced renal renin mRNA levels as well as inflammatory marker toll-like receptor 4 (TLR4) mRNA levels and reduced blood pressure in BPH/2J mice, but not in normotensive BPH/3J mice [ 241 ]. The mimic injection also abolished the blood pressure-reducing effect of enalaprilat, suggesting that the antihypertensive effect of miR-181a is mediated by RAS inhibition [ 241 ].…”

Section: Micrornas In the Regulation Of Ras-induced Cardiac Remodellingmentioning

confidence: 99%

“…miR-181a mimic injection reduced renal renin mRNA levels as well as inflammatory marker toll-like receptor 4 (TLR4) mRNA levels and reduced blood pressure in BPH/2J mice, but not in normotensive BPH/3J mice [ 241 ]. The mimic injection also abolished the blood pressure-reducing effect of enalaprilat, suggesting that the antihypertensive effect of miR-181a is mediated by RAS inhibition [ 241 ]. The level of miR-181a is likely to be under the inhibitory influence of sympathetic stimulation, as renal denervation increased miR-181a levels [ 241 ].…”

Section: Micrornas In the Regulation Of Ras-induced Cardiac Remodellingmentioning

confidence: 99%

“…The mimic injection also abolished the blood pressure-reducing effect of enalaprilat, suggesting that the antihypertensive effect of miR-181a is mediated by RAS inhibition [ 241 ]. The level of miR-181a is likely to be under the inhibitory influence of sympathetic stimulation, as renal denervation increased miR-181a levels [ 241 ]. miR-181a was also found to be one of the TLR4-responsive miRNAs which is downregulated in patients with coronary artery disease (CAD), along with miR-31, miR-16 and miR-145, making it a promising biomarker candidate [ 242 ].…”

Section: Micrornas In the Regulation Of Ras-induced Cardiac Remodellingmentioning

confidence: 99%

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The Impact of microRNAs in Renin–Angiotensin-System-Induced Cardiac Remodelling

Adamcová

Kawano

Šimko

2021

IJMS

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Current knowledge on the renin–angiotensin system (RAS) indicates its central role in the pathogenesis of cardiovascular remodelling via both hemodynamic alterations and direct growth and the proliferation effects of angiotensin II or aldosterone resulting in the hypertrophy of cardiomyocytes, the proliferation of fibroblasts, and inflammatory immune cell activation. The noncoding regulatory microRNAs has recently emerged as a completely novel approach to the study of the RAS. A growing number of microRNAs serve as mediators and/or regulators of RAS-induced cardiac remodelling by directly targeting RAS enzymes, receptors, signalling molecules, or inhibitors of signalling pathways. Specifically, microRNAs that directly modulate pro-hypertrophic, pro-fibrotic and pro-inflammatory signalling initiated by angiotensin II receptor type 1 (AT1R) stimulation are of particular relevance in mediating the cardiovascular effects of the RAS. The aim of this review is to summarize the current knowledge in the field that is still in the early stage of preclinical investigation with occasionally conflicting reports. Understanding the big picture of microRNAs not only aids in the improved understanding of cardiac response to injury but also leads to better therapeutic strategies utilizing microRNAs as biomarkers, therapeutic agents and pharmacological targets

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Mast cell‐derived exosomal miR‐181a‐5p modulated trophoblast cell viability, migration, and invasion via YY1/MMP‐9 axis

Wang¹,

Chen²

2022

Clinical Laboratory Analysis

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Background Mast cells regulate the process of preeclampsia (PE). Since we previously identified mast cells specifically expressing miR‐181a‐5p in the placenta of PE patients, it is plausible to examine the effect and mechanism of mast cell‐derived exosomal miR‐181a‐5p on trophoblast cells. Methods The miR‐181a‐5p and YY1 levels were determined by quantitative real‐time reverse transcription‐polymerase chain reaction. Exosomes were identified by transmission electron microscopy, Western blot, and PKH‐26 labeling. Mast cells or trophoblast cell malignant phenotype were detected using 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide, wound healing, and Transwell assays. Quantification of YY1 and metastasis‐related proteins was performed using Western blot. TargetScan, JASPAR, dual‐luciferase reporter genes, and chromatin immunoprecipitation were exploited to verify the relationship between miR‐181a‐5p, YY1, and MMP‐9. Results MiR‐181a‐5p was overexpressed in mast cells of PE patients. Overexpressed miR‐181a‐5p restrained mast cell viability. Mast cell exosomes were successfully isolated, containing high expressions of CD63 and HSP70 and low expression of Calnexin and could be transported to the cytoplasm of trophoblast cells. Mast cell exosomes attenuated the viability, migration, and invasion of HTR‐8/SVneo cells, inhibited YY1, N‐cadherin, Vimentin, and MMP‐9 protein expressions, and promoted E‐cadherin protein expression. The effect of exosomes was enhanced by miR‐181a‐5p mimic but was reversed by miR‐181a‐5p inhibitor. MiR‐181a‐5p targeted YY1 which bound to the MMP‐9 promoter. Overexpressed YY1 in HTR‐8/SVneo cells accelerated the malignant phenotype of the cells and reversed the regulatory effects of exosomal miR‐181a‐5p. Conclusion Mast cell‐derived exosomal miR‐181a‐5p modulates HTR‐8/SVneo cell viability, migration, and invasion via YY1/MMP‐9.

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

Cited by 13 publications

References 30 publications

Deficiency of MicroRNA-181a Results in Transcriptome-Wide Cell Specific Changes in the Kidney that Lead to Elevated Blood Pressure and Salt Sensitivity

Deficiency of MicroRNA-181a Results in Transcriptome-Wide Cell Specific Changes in the Kidney that Lead to Elevated Blood Pressure and Salt Sensitivity

The Impact of microRNAs in Renin–Angiotensin-System-Induced Cardiac Remodelling

Mast cell‐derived exosomal miR‐181a‐5p modulated trophoblast cell viability, migration, and invasion via YY1/MMP‐9 axis

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