Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10799205 | Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | 2014 | 10 Pages |
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 3â²UTR. 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 5â² 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.
Keywords
qPCRSMITNFAT5ROMKrelative luciferase unitmicroRNA recognition elementIsomiRKv1.3MRE1-desamino-8-d-arginine vasopressinSGK1RLUPAFAH1B1TonEBPDDAVPSCN5AAVPDcxLNA3′-untranslated region3′UTRENaCquantitative real-time RT-PCRAldose reductaseLocked Nucleic AcidTransgenicOsmoregulationdoublecortinUrine concentrationwild typevasopressinarginine vasopressinepithelial sodium channel
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Authors
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,