title: A microRNA-30e/mitochondrial uncoupling protein 2 axis mediates TGF-β1-induced tubular epithelial cell extracellular matrix production and kidney fibrosis.
abstract: Mitochondria dysfunction has been reported in various kidney diseases but how it leads to kidney fibrosis and how this is regulated is unknown. Here we found that mitochondrial uncoupling protein 2 (UCP2) was induced in kidney tubular epithelial cells after unilateral ureteral obstruction in mice and that mice with ablated UCP2 resisted obstruction-induced kidney fibrosis. We tested this association further in cultured NRK-52E cells and found that TGF-β1 remarkably induced UCP2 expression. Knockdown of UCP2 largely abolished the effect of TGF-β1, whereas overexpression of UCP2 promoted tubular cell phenotype changes. Analysis using a UCP2 mRNA-3'-untranslated region luciferase construct showed that UCP2 mRNA is a direct target of miR-30e. MiR-30e was downregulated in tubular cells from fibrotic kidneys and TGF-β1-treated NRK-52E cells. A miR-30e mimic significantly inhibited TGF-β1-induced tubular-cell epithelial-mesenchymal transition, whereas a miR-30e inhibitor imitated TGF-β1 effects. Finally, genipin, an aglycone UCP2 inhibitor, significantly ameliorated kidney fibrosis in mice. Thus, the miR-30e/UCP2 axis has an important role in mediating TGF-β1-induced epithelial-mesenchymal transition and kidney fibrosis. Targeting this pathway may shed new light for the future of fibrotic kidney disease therapy.
authors.affiliation: Center of Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Wenjing
authors.initials: W
authors.lastname: Qiu
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Ping
authors.initials: P
authors.lastname: Wen
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.forename: Hongdi
authors.initials: H
authors.lastname: Cao
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.forename: Weichun
authors.initials: W
authors.lastname: He
authors.forename: Chenyu
authors.initials: C
authors.lastname: Zhang
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
authors.forename: Junwei
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D039823:Iridoids / Q000494:pharmacology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D014517:Ureteral Obstruction / Q000150:complications / Q000235:genetics / Q000378:metabolism
chemical_list: D007473:Ion Channels; D039823:Iridoids; C556157:MIRN30 microRNA, rat; D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; C007834:genipin