miR-324-5p and miR-30c-2-3p Alter Renal Mineralocorticoid Receptor Signaling under Hypertonicity

The Mineralocorticoid Receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron, but mechanisms regulating MR expression are still poorly understood. We previously showed that RNA Binding Proteins (RBPs) regulate MR expression at the post-transcriptional level in respon...

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Bibliographic Details
Published in:	Cells (Basel, Switzerland) Vol. 11; no. 9; p. 1377
Main Authors:	Vu, Thi An, Lema, Ingrid, Hani, Imene, Cheval, Lydie, Atger-Lallier, Laura, Souvannarath, Vilayvane, Perrot, Julie, Souvanheuane, Mélanie, Marie, Yannick, Fabrega, Sylvie, Blanchard, Anne, Bouligand, Jérôme, Kamenickỷ, Peter, Crambert, Gilles, Martinerie, Laetitia, Lombès, Marc, Viengchareun, Say
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 19-04-2022 MDPI
Subjects:	Aldosterone Aldosterone - metabolism Animals Antigens Binding sites Furosemide Gene expression High-throughput screening HuR protein Hypertonicity Kidney - metabolism Kidneys Kinases Life Sciences Mice MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism mineralocorticoid receptor Mineralocorticoids - metabolism miRNA Post-transcription post-transcriptional regulation Receptors, Mineralocorticoid - genetics Receptors, Mineralocorticoid - metabolism RNA-binding protein Signal Transduction Sodium - metabolism sodium reabsorption Transfection France microRNAs sodium reabsorption mineralocorticoid receptor aldosterone post-transcriptional regulation hypertonicity
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Summary:	The Mineralocorticoid Receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron, but mechanisms regulating MR expression are still poorly understood. We previously showed that RNA Binding Proteins (RBPs) regulate MR expression at the post-transcriptional level in response to variations of extracellular tonicity. Herein, we highlight a novel regulatory mechanism involving the recruitment of microRNAs (miRNAs) under hypertonicity. RT-qPCR validated miRNAs candidates identified by high throughput screening approaches and transfection of a luciferase reporter construct together with miRNAs Mimics or Inhibitors demonstrated their functional interaction with target transcripts. Overexpression strategies using Mimics or lentivirus revealed the impact on MR expression and signaling in renal KC3AC1 cells. miR-324-5p and miR-30c-2-3p expression are increased under hypertonicity in KC3AC1 cells. These miRNAs directly affect (MR) transcript stability, act with Tis11b to destabilize MR transcript but also repress (HuR) transcript, which enhances MR expression and signaling. Overexpression of miR-324-5p and miR-30c-2-3p alter MR expression and signaling in KC3AC1 cells with blunted responses in terms of aldosterone-regulated genes expression. We also confirm that their expression is increased by hypertonicity in vivo in the kidneys of mice treated with furosemide. These findings may have major implications for the pathogenesis of renal dysfunctions, sodium retention, and mineralocorticoid resistance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2073-4409 2073-4409
DOI:	10.3390/cells11091377