Abstract
The TGF-β/Smad3 pathway plays a major role in tissue fibrosis, but the precise mechanisms are not fully understood. Here we identified microRNA miR-433 as an important component of TGF-β/Smad3-driven renal fibrosis. The miR-433 was upregulated following unilateral ureteral obstruction, a model of aggressive renal fibrosis. In vitro, overexpression of miR-433 enhanced TGF-β1-induced fibrosis, whereas knockdown of miR-433 suppressed this response. Furthermore, Smad3, but not Smad2, bound to the miR-433 promoter to induce its expression. Delivery of an miR-433 knockdown plasmid to the kidney by ultrasound microbubble-mediated gene transfer suppressed the induction and progression of fibrosis in the obstruction model. The antizyme inhibitor Azin1, an important regulator of polyamine synthesis, was identified as a target of miR-433. Overexpression of miR-433 suppressed Azin1 expression, while, in turn, Azin1 overexpression suppressed TGF-β signaling and the fibrotic response. Thus, miR-433 is an important component of TGF-β/Smad3-induced renal fibrosis through the induction of a positive feedback loop to amplify TGF-β/Smad3 signaling, and may be a potential therapeutic target in tissue fibrosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Glomerular Basement Membrane Disease / genetics
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Anti-Glomerular Basement Membrane Disease / metabolism
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Anti-Glomerular Basement Membrane Disease / pathology
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Binding Sites
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Disease Models, Animal
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Doxorubicin
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Fibrosis
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Kidney / metabolism*
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Kidney / pathology
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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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Male
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Knockout
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Promoter Regions, Genetic
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RNA Interference
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Rats
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Signal Transduction
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Smad2 Protein / deficiency
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Smad2 Protein / genetics
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Smad2 Protein / metabolism
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Smad3 Protein / deficiency
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Smad3 Protein / genetics
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Smad3 Protein / metabolism*
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Smad7 Protein / genetics
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Smad7 Protein / metabolism
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Time Factors
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Transfection
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism*
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Up-Regulation
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Ureteral Obstruction / complications
Substances
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Carrier Proteins
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MicroRNAs
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Mirn433 microRNA, mouse
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Smad2 Protein
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Smad2 protein, mouse
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Smad2 protein, rat
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Smad3 Protein
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Smad3 protein, mouse
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Smad3 protein, rat
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Smad7 Protein
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TGFB1 protein, human
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Tgfb1 protein, mouse
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Transforming Growth Factor beta1
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ornithine decarboxylase antizyme inhibitor
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Doxorubicin