title: 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.
authors.affiliation: School of Nursing, The Third Military Medical University, Chongqing 400038, China; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Jinpao
authors.initials: J
authors.lastname: Hou
authors.affiliation: The First Affiliated Hospital of Xiamen University, Xiamen 361005, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital of Xiamen University, Xiamen 361005, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China; Fujian Provincial Transgenic Core, Xiamen University Laboratory Animal Center, Xiang'an, Xiamen 361102, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China; Fujian Provincial Transgenic Core, Xiamen University Laboratory Animal Center, Xiang'an, Xiamen 361102, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Zhongshan Hospital, Xiamen University, Xiamen 361005, China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Nephrology and Basic Science Laboratory, Union Hospital, Fujian Medical University, Fuzhou 350001, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
authors.affiliation: School of Nursing, The Third Military Medical University, Chongqing 400038, China; Fujian Provincial Transgenic Core, Xiamen University Laboratory Animal Center, Xiang'an, Xiamen 361102, China. Electronic address: jyqy2008@gmail.com.
authors.forename: James Y
authors.initials: JY
authors.lastname: Yang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D003401:Creatine / Q000097:blood / Q000652:urine; D044127:Epigenesis, Genetic; D015870:Gene Expression / Q000187:drug effects; D007438:Introns / Q000235:genetics*; D007671:Kidney Concentrating Ability / Q000235:genetics*; D007672:Kidney Cortex / Q000378:metabolism; D007679:Kidney Medulla / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D064587:Osmoregulation / Q000235:genetics*; D011188:Potassium / Q000097:blood / Q000652:urine; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000235:genetics; D012964:Sodium / Q000097:blood / Q000652:urine; D014157:Transcription Factors / Q000235:genetics*; D014508:Urea / Q000097:blood / Q000652:urine
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; C576133:Mirn466 microRNA, mouse; D050778:NFATC Transcription Factors; D012097:Repressor Proteins; C527638:Sfmbt2 protein, mouse; D014157:Transcription Factors; D001127:Arginine Vasopressin; D014508:Urea; D012964:Sodium; D003401:Creatine; D011188:Potassium
keywords: Nfat5/OREBP/TonEBP; Osmoregulation; Sfmbt2 10th intron-hosted miRNA cluster (C2MC); Urine concentration; Vasopressin; miR-466a-3p