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Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury.
- Source :
-
American journal of physiology. Renal physiology [Am J Physiol Renal Physiol] 2009 Sep; Vol. 297 (3), pp. F729-39. Date of Electronic Publication: 2009 Jun 24. - Publication Year :
- 2009
-
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.
- Subjects :
- Acetylcysteine pharmacology
Amides pharmacology
Animals
Antioxidants pharmacology
Biphenyl Compounds pharmacology
Cell Line
Cell Transdifferentiation
Diabetes Mellitus, Experimental enzymology
Diabetes Mellitus, Experimental pathology
Diabetes Mellitus, Type 1 drug therapy
Diabetes Mellitus, Type 1 enzymology
Diabetes Mellitus, Type 1 pathology
Diabetes Mellitus, Type 2 drug therapy
Diabetes Mellitus, Type 2 enzymology
Diabetes Mellitus, Type 2 pathology
Diabetic Nephropathies etiology
Diabetic Nephropathies pathology
Diabetic Nephropathies prevention & control
Enzyme Inhibitors pharmacology
Extracellular Matrix Proteins genetics
Fibrosis
Gene Expression Regulation
Histone Deacetylase 2
Histone Deacetylase Inhibitors
Histone Deacetylases genetics
Humans
Hydroxamic Acids pharmacology
Kidney drug effects
Kidney pathology
Male
Mice
RNA Interference
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species metabolism
Recombinant Proteins metabolism
Repressor Proteins antagonists & inhibitors
Repressor Proteins genetics
Valproic Acid pharmacology
Diabetes Mellitus, Experimental complications
Diabetes Mellitus, Type 1 complications
Diabetes Mellitus, Type 2 complications
Diabetic Nephropathies enzymology
Histone Deacetylases metabolism
Kidney enzymology
Repressor Proteins metabolism
Transforming Growth Factor beta1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1466
- Volume :
- 297
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Renal physiology
- Publication Type :
- Academic Journal
- Accession number :
- 19553350
- Full Text :
- https://doi.org/10.1152/ajprenal.00086.2009