Abstract
TGF-β1 upregulates microRNA-192 (miR-192) in cultured glomerular mesangial cells and in glomeruli from diabetic mice. miR-192 not only increases collagen expression by targeting the E-box repressors Zeb1/2 but also modulates other renal miRNAs, suggesting that it may be a therapeutic target for diabetic nephropathy. We evaluated the efficacy of a locked nucleic acid (LNA)-modified inhibitor of miR-192, designated LNA-anti-miR-192, in mouse models of diabetic nephropathy. LNA-anti-miR-192 significantly reduced levels of miR-192, but not miR-194, in kidneys of both normal and streptozotocin-induced diabetic mice. In the kidneys of diabetic mice, inhibition of miR-192 significantly increased Zeb1/2 and decreased gene expression of collagen, TGF-β, and fibronectin; immunostaining confirmed the downregulation of these mediators of renal fibrosis. Furthermore, LNA-anti-miR-192 attenuated proteinuria in these diabetic mice. In summary, the specific reduction of renal miR-192 decreases renal fibrosis and improves proteinuria, lending support for the possibility of an anti-miRNA-based translational approach to the treatment of diabetic nephropathy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Albuminuria / metabolism
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Albuminuria / prevention & control
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Animals
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Collagen / metabolism
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Diabetes Mellitus, Experimental / chemically induced
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Diabetes Mellitus, Experimental / complications*
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Diabetes Mellitus, Type 1 / chemically induced
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Diabetes Mellitus, Type 1 / complications
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Diabetic Nephropathies / metabolism
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Diabetic Nephropathies / pathology*
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Diabetic Nephropathies / prevention & control*
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Disease Models, Animal
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Fibronectins / metabolism
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Fibrosis
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Homeodomain Proteins / metabolism
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Kidney / drug effects
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Kidney / metabolism
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Kidney / pathology*
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Kruppel-Like Transcription Factors / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred DBA
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MicroRNAs / antagonists & inhibitors*
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MicroRNAs / drug effects*
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Oligonucleotides / pharmacology*
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Proteinuria / metabolism
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Proteinuria / prevention & control
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Repressor Proteins / metabolism
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Streptozocin / adverse effects
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Transforming Growth Factor beta / metabolism
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Zinc Finger E-box Binding Homeobox 2
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Zinc Finger E-box-Binding Homeobox 1
Substances
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Fibronectins
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Homeodomain Proteins
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Kruppel-Like Transcription Factors
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MicroRNAs
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Mirn192 microRNA, mouse
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Oligonucleotides
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Repressor Proteins
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Transforming Growth Factor beta
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ZEB1 protein, mouse
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ZEB2 protein, mouse
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Zinc Finger E-box Binding Homeobox 2
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Zinc Finger E-box-Binding Homeobox 1
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locked nucleic acid
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Streptozocin
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Collagen