Abstract
Enhanced transforming growth factor-β1 (TGF-β1) expression in renal cells promotes fibrosis and hypertrophy during the progression of diabetic nephropathy. The TGF-β1 promoter is positively controlled by the E-box regulators, upstream stimulatory factors (USFs), in response to diabetic (high glucose) conditions; however, it is not clear whether TGF-β1 is autoregulated by itself. As changes in microRNAs (miRNAs) have been implicated in kidney disease, we tested their involvement in this process. TGF-β1 levels were found to be upregulated by microRNA-192 (miR-192) or miR-200b/c in mouse mesangial cells. Amounts of miR-200b/c were increased in glomeruli from type 1 (streptozotocin) and type 2 (db/db) diabetic mice, and in mouse mesangial cells treated with TGF-β1 in vitro. Levels of miR-200b/c were also upregulated by miR-192 in the mesangial cells, suggesting that miR-200b/c are downstream of miR-192. Activity of the TGF-β1 promoter was upregulated by TGF-β1 or miR-192, demonstrating that the miR-192-miR-200 cascade induces TGF-β1 expression. TGF-β1 increased the occupancy of activators USF1 and Tfe3, and decreased that of the repressor Zeb1 on the TGF-β1 promoter E-box binding sites. Inhibitors of miR-192 decreased the expression of miR-200b/c, Col1a2, Col4a1, and TGF-β1 in mouse mesangial cells, and in mouse kidney cortex. Thus, miRNA-regulated circuits may amplify TGF-β1 signaling, accelerating chronic fibrotic diseases such as diabetic nephropathy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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3' Untranslated Regions
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Binding Sites
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Cells, Cultured
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Collagen Type I / metabolism
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Collagen Type IV / metabolism
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Diabetes Mellitus, Experimental / chemically induced
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Diabetes Mellitus, Experimental / genetics
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Diabetes Mellitus, Experimental / metabolism*
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Type 1 / chemically induced
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Diabetes Mellitus, Type 1 / genetics
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Diabetes Mellitus, Type 1 / metabolism*
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Diabetes Mellitus, Type 1 / pathology
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism*
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Diabetes Mellitus, Type 2 / pathology
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Diabetic Nephropathies / genetics
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Diabetic Nephropathies / metabolism*
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Diabetic Nephropathies / pathology
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Fibrosis
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Homeodomain Proteins / metabolism
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Homeostasis
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Kruppel-Like Transcription Factors / metabolism
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Mesangial Cells / metabolism*
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Mice
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MicroRNAs / metabolism*
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Mutation
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Oligonucleotides / metabolism
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Promoter Regions, Genetic
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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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Upstream Stimulatory Factors / metabolism
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Zinc Finger E-box-Binding Homeobox 1
Substances
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3' Untranslated Regions
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Collagen Type I
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Collagen Type IV
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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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Mirn200 microRNA, mouse
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Oligonucleotides
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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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Upstream Stimulatory Factors
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Usf1 protein, mouse
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ZEB1 protein, mouse
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Zinc Finger E-box-Binding Homeobox 1
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Tcfe3 protein, mouse