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Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-[beta]1-induced renal injury
- Source :
- The American Journal of Physiology. Sept, 2009, Vol. 297 Issue 3, pF729, 11 p.
- 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)-[beta]1 and determined the role of reactive oxygen species (ROS) as mediators of HDAC activation. In streptozotocin (STZ)-induced diabetic kidneys and TGF-[beta]1-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-[beta]1-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-acetylcystein, almost completely reduced TGF-[beta]1-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-[beta]1-induced activation of HDAC-2. reactive oxygen species; extracellular matrix; epithelial-to-mesenchyreal transition
- Subjects :
- Gene expression -- Research
Gene expression -- Physiological aspects
Diabetes -- Research
Diabetes -- Physiological aspects
Transforming growth factors -- Research
Transforming growth factors -- Physiological aspects
Kidney diseases -- Research
Kidney diseases -- Physiological aspects
Histones -- Research
Histones -- Physiological aspects
Biological sciences
Subjects
Details
- Language :
- English
- ISSN :
- 00029513
- Volume :
- 297
- Issue :
- 3
- Database :
- Gale General OneFile
- Journal :
- The American Journal of Physiology
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.208640684