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Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury.
Am J Physiol Renal Physiol. 2009 Sep; 297(3):F729-39.AJ

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.

Authors+Show Affiliations

Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19553350

Citation

Noh, Hyunjin, et al. "Histone Deacetylase-2 Is a Key Regulator of Diabetes- and Transforming Growth Factor-beta1-induced Renal Injury." American Journal of Physiology. Renal Physiology, vol. 297, no. 3, 2009, pp. F729-39.
Noh H, Oh EY, Seo JY, et al. Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. Am J Physiol Renal Physiol. 2009;297(3):F729-39.
Noh, H., Oh, E. Y., Seo, J. Y., Yu, M. R., Kim, Y. O., Ha, H., & Lee, H. B. (2009). Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. American Journal of Physiology. Renal Physiology, 297(3), F729-39. https://doi.org/10.1152/ajprenal.00086.2009
Noh H, et al. Histone Deacetylase-2 Is a Key Regulator of Diabetes- and Transforming Growth Factor-beta1-induced Renal Injury. Am J Physiol Renal Physiol. 2009;297(3):F729-39. PubMed PMID: 19553350.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. AU - Noh,Hyunjin, AU - Oh,Eun Young, AU - Seo,Ji Yeon, AU - Yu,Mi Ra, AU - Kim,Young Ok, AU - Ha,Hunjoo, AU - Lee,Hi Bahl, Y1 - 2009/06/24/ PY - 2009/6/26/entrez PY - 2009/6/26/pubmed PY - 2009/9/9/medline SP - F729 EP - 39 JF - American journal of physiology. Renal physiology JO - Am J Physiol Renal Physiol VL - 297 IS - 3 N2 - 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. SN - 1522-1466 UR - https://www.unboundmedicine.com/medline/citation/19553350/Histone_deacetylase_2_is_a_key_regulator_of_diabetes__and_transforming_growth_factor_beta1_induced_renal_injury_ L2 - https://journals.physiology.org/doi/10.1152/ajprenal.00086.2009?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -