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

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• 作者：Yu Luo ; Ying Liu ; Meng Liu ; Jie Wei ; Yunyun Zhang ; Jinpao Hou ; Weifeng Huang ; Tao Wang ; Xun Li ; Ying He ; Feng Ding ; Li Yuan ; Jianchun Cai ; Feng Zheng ; James Y. Yang
• 关键词：3&prime ; UTR ; 3&prime ; -untranslated region ; AVP ; arginine vasopressin ; Aqp1/2/3 ; aquaporin-1/2/3 ; Ar ; aldose reductase ; Cdkn1c or p57 ; Cyclin-dependent kinase inhibitor 1C ; C2MC ; Chromosome 2 miRNA cluster ; Dcx ; Doublecortin ; ddAVP ; 1-desamino-8-d-arginine vasopressin ; ENaC ; epithelial sodium channel ; isomiR ; miRNA isoform ; Kv1.3 ; Potassium voltage-gated channel ; shaker-related subfamily ; member 3 ; LNA ; locked nucleic acid ; MRE ; microRNA recognition element ; Nfat5 ; nuclear factor of activated T c
• 刊名：Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
• 出版年：February, 2014
• 年：2014
• 卷：1839
• 期：2
• 页码：97-106
• 全文大小：1192 K

文摘

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鈥睻TR. 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鈥?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.