OR28-04 Exploring the Physiological Downregulation of Mineralocorticoid Receptor Expression at Birth : Role of miR-409-3p and miR-431-5p

Abstract Disclosure: L. Martinerie: None. I. Hani: None. L. Guyon: None. N. Cherradi: None. T. Vu: None. J. Perrot: None. T. Rajkumar: None. E. Pussard: None. P. Boileau: None. R. Brillet: None. J. Guegan: None. J. Bouligand: None. P. Kamenicky: None. M. Lombes: None. S. Viengchareun: None. Aldosterone regulates sodium homeostasis by binding to the Mineralocorticoid Receptor (MR). We previously identified a critical temporal window during renal development when MR expression is low, explaining the physiological sodium losses observed in newborns at birth. However, the molecular mechanisms governing MR expression remain unclear. Here, we report the involvement of two microRNAs (miRNAs), miR-409-3p and miR-431-5p, in regulating MR expression during early renal development. Using miRNA sequencing, we identified these miRNAs as upregulated on postnatal day 0 (D0) compared to day 8 (D8). RT-qPCR validated their differential expression, while luciferase reporter assays confirmed their functional interaction with MR transcripts. Functional studies using miRNA mimics and inhibitors revealed that miR-409-3p and miR-431-5p modulate MR expression and signaling in primary renal cell cultures. Specifically, their increased expression at D0 destabilizes MR transcripts and decreases MR expression and signaling, while their decreased expression at D8 leads to MR stabilization and enhanced mineralocorticoid signaling. Notably, digital droplet PCR (ddPCR) analysis of neonatal urine samples from the PREMALDO cohort demonstrated that these miRNAs are highly expressed at birth but decrease gradually postnatally. To explore the broader regulatory network, we performed RNA sequencing to identify differentially expressed genes (DEGs) between D0 and D8. Cross-referencing DEGs with the predicted targets of miR-409-3p and miR-431-5p yielded 83 differentially expressed target genes. Functional annotation of these genes highlighted significant enrichment in pathways related to kidney development, sodium transport and homeostasis. Our findings identify miR-409-3p and miR-431-5p as key regulators of MR expression and mineralocorticoid signaling during renal development. These miRNAs could serve as potential predictive and non-invasive biomarkers of renal maturity and mineralocorticoid signaling efficiency in premature infants. Presentation: Monday, July 14, 2025