Sfmbt2 10th intron-hosted miR-466(a/e)-3p are important epigenetic regulators of Nfat5 signaling, osmoregulation and urine concentration in mice

Abstract

Sfmbt2-hosted miR-466a-3p and its close relatives are often among the most significantly up-regulated or down-regulated miRNAs in responses to numerous deleterious environmental stimuli. The exact roles of these miRNAs in cellular stress responses, however, are not clear. Here we showed that many Sfmbt2-hosted miRNAs were highly hypertonic stress responsive in vitro and in vivo. In renal medulla, water deprivation induced alterations in the expression of miR-466(a/b/c/e/p)-3p in a pattern similar to that of miR-200b-3p, a known regulator of osmoresponsive transcription factor Nfat5. Remarkably, exposure of mIMCD3 cells to an arginine vasopressin analog time-dependently down-regulated the expression of miR-466(a/b/c/e/p)-3p and miR-200b-3p, which provides a novel regulatory mechanism for these osmoresponsive miRNAs. In cultured mIMCD3 cells we further demonstrated that miR-466a-3p and miR-466g were capable of targeting Nfat5 by interacting with its 3'UTR. In transgenic mice overexpressing miR-466a-3p, significant down-regulation of Nfat5 and many other osmoregulation-related genes was observed in both the renal cortex and medulla. Moreover, sustained transgenic over-expression of miR-466a-3p was found to be associated with polydipsia, polyuria and disturbed ion homeostasis and kidney morphology. Since the mature sequence of miR-466a-3p is completely equivalent to that of miR-466e-3p and that the seed sequence of miR-466a-3p is completely equivalent to that of miR-297(a/b/c)-3p, miR-466d-3p, miR-467g and miR-669d-3p, and that miR-466a-3p differs from miR-466(b/c/p)-3p only in a 5' nucleotide, we propose that miR-466a-3p and many of its close relatives are important epigenetic regulators of renal Nfat5 signaling, osmoregulation and urine concentration in mice.

Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing Through Modulating MicroRNAs

“…6 A – D ). As a matter of fact, these two miR families have been reported to similarly respond to detrimental cellular stress and share comment target genes, for example, Nfat5 in immune cells and Dcx and Patah1b1 in neural stem cells (57,58). Our study delineated an important regulatory mechanism of miR-466 and miR-200 against the diabetic environment, in which the UPR transducer IRE1α functions as the upstream regulator and the proangiogenic factor ANGPT1 acts as an effector.…”

miR‐466 is putative negative regulator of Coxsackie virus and Adenovirus Receptor

“…In another study, another member, mmu‐miR‐669c was shown to be associated with the regulation of glutathione metabolism in the liver of aging mice [62]. Recent report also showed that mmu‐miR‐466(a/e)‐3p were important epigenetic regulators of renal Nfat5 signaling, osmoregulation and urine concentration in mice [63]. Therefore, this is the first report showing the function of miR‐466 of the gene family – miR‐467 in human.…”

Aldosterone‐induced microRNAs act as feedback regulators of mineralocorticoid receptor signaling in kidney epithelia

“…Nevertheless, this cluster has been studied in mice and shown to play a role in osmoregulation in the kidney. 82 Another miR-466 isoform (not part of this cluster), miR-466g was also shown to target SGK1. 83 As miRs-466a/e & b/c were upregulated after a 24-hours aldosterone stimulation, our focus shifted to the miR-466 F I G U R E 6 Heatmap of % of miRs predicted to bind to the mRNAs listed (from miRDB predictions).…”