Abstract
Excessive accumulation of extracellular matrix (ECM) in the kidneys and epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells contributes to the renal fibrosis that is associated with diabetic nephropathy. Histone deacetylase (HDAC) determines the acetylation status of histones and thereby controls the regulation of gene expression. This study examined the effect of HDAC inhibition on renal fibrosis induced by diabetes or transforming growth factor (TGF)-beta1 and determined the role of reactive oxygen species (ROS) as mediators of HDAC activation. In streptozotocin (STZ)-induced diabetic kidneys and TGF-beta1-treated normal rat kidney tubular epithelial cells (NRK52-E), we found that trichostatin A, a nonselective HDAC inhibitor, decreased mRNA and protein expressions of ECM components and prevented EMT. Valproic acid and class I-selective HDAC inhibitor SK-7041 also showed similar effects in NRK52-E cells. Among the six HDACs tested (HDAC-1 through -5 and HDAC-8), HDAC-2 activity significantly increased in the kidneys of STZ-induced diabetic rats and db/db mice and TGF-beta1-treated NRK52-E cells. Levels of mRNA expression of fibronectin and alpha-smooth muscle actin were decreased, whereas E-cadherin mRNA was increased when HDAC-2 was knocked down using RNA interference in NRK52-E cells. Interestingly, hydrogen peroxide increased HDAC-2 activity, and the treatment with an antioxidant, N-acetylcysteine, almost completely reduced TGF-beta1-induced activation of HDAC-2. These findings suggest that HDAC-2 plays an important role in the development of ECM accumulation and EMT in diabetic kidney and that ROS mediate TGF-beta1-induced activation of HDAC-2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / pharmacology
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Amides / pharmacology
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Animals
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Antioxidants / pharmacology
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Biphenyl Compounds / pharmacology
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Cell Line
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Cell Transdifferentiation
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Diabetes Mellitus, Experimental / complications*
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Diabetes Mellitus, Experimental / enzymology
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Type 1 / complications*
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Diabetes Mellitus, Type 1 / drug therapy
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Diabetes Mellitus, Type 1 / enzymology
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Diabetes Mellitus, Type 1 / pathology
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Diabetes Mellitus, Type 2 / complications*
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Diabetes Mellitus, Type 2 / drug therapy
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Diabetes Mellitus, Type 2 / enzymology
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Diabetes Mellitus, Type 2 / pathology
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Diabetic Nephropathies / enzymology*
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Diabetic Nephropathies / etiology
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Diabetic Nephropathies / pathology
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Diabetic Nephropathies / prevention & control
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Enzyme Inhibitors / pharmacology
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Extracellular Matrix Proteins / genetics
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Fibrosis
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Gene Expression Regulation
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Histone Deacetylase 2
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Histone Deacetylase Inhibitors
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Humans
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Hydroxamic Acids / pharmacology
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Kidney / drug effects
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Kidney / enzymology*
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Kidney / pathology
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Male
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Mice
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RNA Interference
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism
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Recombinant Proteins / metabolism
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Transforming Growth Factor beta1 / metabolism*
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Valproic Acid / pharmacology
Substances
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Amides
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Antioxidants
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Biphenyl Compounds
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Enzyme Inhibitors
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Extracellular Matrix Proteins
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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RNA, Messenger
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Reactive Oxygen Species
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Recombinant Proteins
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Repressor Proteins
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SK-7041
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Transforming Growth Factor beta1
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trichostatin A
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Valproic Acid
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Hdac2 protein, mouse
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Hdac2 protein, rat
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Histone Deacetylase 2
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Histone Deacetylases
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Acetylcysteine