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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Disease Models, Animal
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Epithelial-Mesenchymal Transition
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Extracellular Matrix / metabolism*
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Fibrosis
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Humans
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Ion Channels / antagonists & inhibitors
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Ion Channels / deficiency
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Ion Channels / genetics
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Ion Channels / metabolism*
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Iridoids / pharmacology
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Kidney Diseases / etiology
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Kidney Diseases / genetics
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Kidney Diseases / metabolism*
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Kidney Diseases / pathology
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Kidney Diseases / prevention & control
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Kidney Tubules / drug effects
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Kidney Tubules / metabolism*
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Kidney Tubules / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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MicroRNAs / metabolism*
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Mitochondrial Proteins / antagonists & inhibitors
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Mitochondrial Proteins / deficiency
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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RNA Interference
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Rats
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Recombinant Proteins / metabolism
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Signal Transduction
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Time Factors
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Transfection
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Transforming Growth Factor beta1 / metabolism*
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Uncoupling Protein 2
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Ureteral Obstruction / complications
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Ureteral Obstruction / genetics
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Ureteral Obstruction / metabolism
Substances
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Ion Channels
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Iridoids
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MIRN30 microRNA, rat
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MicroRNAs
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Mirn30d microRNA, mouse
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Mitochondrial Proteins
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Recombinant Proteins
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TGFB1 protein, human
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Transforming Growth Factor beta1
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UCP2 protein, human
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Ucp2 protein, mouse
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Ucp2 protein, rat
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Uncoupling Protein 2
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genipin