Project description:Aldosterone controls sodium homeostasis by binding to the Mineralocorticoid Receptor (MR). We previously identified a specific temporal window during renal development when MR expression is low, explaining the physiological sodium losses observed in newborns at birth. However, underlying molecular mechanisms controlling MR expression remain unknown. Recently, we demonstrated in adult renal KC3AC1 cell line that MR expression is controlled by microRNAs (miR-30c-2-3p and miR-324-5p) in response to tonicity. Herein, we highlight the involvement of two microRNAs (miR-409-3p and miR-431-5p) in the regulation of MR expression during the neonatal period. RT-qPCR validated candidates microRNAs identified by high throughput screening approach and transfection of a luciferase reporter construct together with miRNAs Mimics or Inhibitors demonstrated their functional interaction with target transcripts. Underexpression strategies using Inhibitors revealed the impact on MR expression and signaling in primary culture renal cells. miR-409-3p and miR-431-5p are increased at D0 in mirror to MR expression. These miRNAs directly affect Nr3c2 (MR) transcript stability and enhances MR expression and signaling at D0. Whereas, overexpression strategies using Mimics, destabilize MR expression and mineralocorticoid signaling in primary culture renal cells at D8. We also confirm that their expression is increased in urine from neonates at birth, an expression that gradually decreased after birth (PREMALDO cohort). Finally, we performed an RNA sequencing to evaluate an integrative network of miRNAs and mRNA differentially expressed between D0 and D8. Differentially expressed genes (DEG) were crossed with the two candidate miRNAs, and 83 differentially expressed target genes (DETG) were obtained. Functional annotation suggested that kidney development and sodium transport/homeostasis pathways were significantly enriched. Our findings provide new predictive and non-invasive biomarkers of renal maturity and mineralocorticoid signaling expression and efficacy in human premature infants.

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Fate (or state) of CA2 neurons in a mineralocorticoid receptor knockout.

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