Abstract
Renal fibrosis results from excessive accumulation of extracellular matrix mainly driven by transforming growth factor-β1 (TGF-β1). Certain microRNAs have been implicated in this disease, and here we examine the role of let-7b. Rat proximal tubular epithelial cells (NRK52E) were treated with TGF-β1 for 3 days to assess the expression of markers of fibrosis and let-7b. These factors were also assessed in two mouse models representing early and more advanced diabetic nephropathy and in the non-diabetic adenine-induced renal fibrosis model. TGF-β1 downregulated the expression of let-7b and induced fibrogenesis in NRK52E cells. Ectopic expression of let-7b repressed TGF-β1 receptor 1 (TGFBR1) expression directly by targeting the two let-7b binding sites in the 3'-untranslated region of that gene, reduced expression of extracellular matrix proteins, decreased SMAD3 activity, and attenuated the profibrotic effects of TGF-β1. Knockdown of let-7b elevated TGFBR1 expression and mimicked some of the profibrotic effects of TGF-β1. Consistent with these observations, let-7b expression was also reduced in models of both diabetic and non-diabetic renal fibrosis with the upregulation of TGFBR1. Thus, let-7b microRNA represents a potential new target for the treatment of renal fibrosis in diabetic and non-diabetic nephropathy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Adenine
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Animals
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Binding Sites
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Cell Line
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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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Disease Models, Animal
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / metabolism
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Fibrosis
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Gene Expression Regulation
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Humans
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Kidney / metabolism*
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Kidney / pathology
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Kidney Tubules / metabolism
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Kidney Tubules / pathology
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Mesangial Cells / metabolism
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Mesangial Cells / pathology
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Mice
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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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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Rats
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism*
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Recombinant Proteins / metabolism
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Renal Insufficiency, Chronic / chemically induced
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Renal Insufficiency, Chronic / genetics
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Renal Insufficiency, Chronic / metabolism*
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Renal Insufficiency, Chronic / pathology
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Signal Transduction
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Smad3 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*
Substances
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3' Untranslated Regions
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Apolipoproteins E
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Extracellular Matrix Proteins
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MIRNLET7 microRNA, rat
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MicroRNAs
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Receptors, Transforming Growth Factor beta
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Recombinant Proteins
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Smad3 Protein
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Smad3 protein, rat
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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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mirnlet7 microRNA, mouse
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, mouse
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Tgfbr1 protein, rat
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Adenine