Histone deacetylase activator

We also thank J. Author Contributions T. The Institute for Diabetes, Obesity, and Metabolism, and,. Ahima, Klaus H.

You can also search for this author in PubMed Google Scholar. Correspondence to Mitchell A. This file contains Supplementary Table 1 and Supplementary Figures with legends. PDF kb. Reprints and Permissions. Alenghat, T. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Download citation. Received : 15 April Accepted : 14 October Published : 26 November Issue Date : 18 December Anyone you share the following link with will be able to read this content:.

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Advanced search. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. Abstract Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications 1 , 2 , 3.

Access through your institution. Buy or subscribe. This is a preview of subscription content. Change institution. Buy article Get time limited or full article access on ReadCube. Figure 1: Ncor1—Hdac3 regulates peripheral clock and circadian physiology. Figure 2: DADm mice exhibit increased energy expenditure. Figure 3: DADm mice are resistant to diet-induced obesity. Figure 4: Activation of Hdac3 by Ncor1 regulates circadian metabolic gene expression in the liver.

References 1 Ripperger, J. Acknowledgements We thank W. Kaestner Authors Theresa Alenghat View author publications. View author publications. Supplementary information. PowerPoint slides PowerPoint slide for Fig. PowerPoint slide for Fig. Rights and permissions Reprints and Permissions. About this article Cite this article Alenghat, T.

Copy to clipboard. Comments By submitting a comment you agree to abide by our Terms and Community Guidelines. Search Search articles by subject, keyword or author. Show results from All journals This journal. Recent studies point to the importance of these enzymes in controlling proliferation and differentiation of various cells 7.

However, the molecular and functional consequences of HDAC inhibition in renal interstitial fibroblasts have not been previously described. As progressive renal interstitial fibrosis is not only the predominant pathological feature of obstructive nephropathy but is also considered as a common final pathway of nearly all forms of CKD, our findings suggest that HDACs may play an essential role in mediating the development of renal interstitial fibrosis in CKD caused by different renal diseases.

This claim was supported by our observations as follows. First, activation of fibroblasts was accompanied by phosphorylation of STAT3 at tyrosine in both cultured renal interstitial fibroblasts and in the fibrotic kidney induced by UUO. The crystal structure of STAT3 shows that acetylated lysine is situated on the external surface of the SH2 domain where tyrosine residue is located As such, these two posttranslational modifications may be mutually exclusive.

STAT3 acetylation on lysine may cause a conformational change that interferes with substrates and ATP to access the catalytic pocket. In this regard, it has been reported that many cytoplasmic and membrane proteins including cytokine receptors also undergo acetylation 16 , 43 , 50 , and this acetylation is associated with inhibition of enzymatic activities.

For example, acetylation of acetyl-CoA synthase 42 and nitric oxide synthase 32 leads to inactivation of these enzymes. HDACs may also indirectly contribute to renal fibrosis by inducing apoptosis and subsequent release of fibrogenic cytokines.

It is well known that ureteral obstruction leads to renal damage, with tubular cell apoptosis occurring as an early event followed by the release of cytokines and chemokines from the injured tubular cell, resulting in inflammatory reaction and interstitial fibrosis 3.

Thus the inhibition of initial apoptosis is likely to limit the generation of signals from dying cells that would subsequently attract and promote the inflammatory response. This, in turn, would prevent the renal accumulation of a number of proapoptotic and profibrotic cytokines.

Recently, Arany et al. In the present study, we examined the effect of TSA on renal tubular apoptosis in a mouse model of renal fibrosis induced by UUO and found that TSA administration at 0.

However, it should be noted that TSA may have a toxic effect on renal epithelial cells when large doses are used.

Dong et al. As such, TSA may have both prosurvival or proapoptotic effects, depending on the concentration used. Although our data suggest that suppression of renal fibroblast activation and inhibition of tubular cell apoptosis serve as the important antifibrotic mechanisms of HDAC inhibitors, other actions of HDAC inhibition may also contribute to this process. Yoshikawa et al. Recently, they further demonstrated that treatment with TSA attenuated the progression of proteinuria and glomerulosclerosis in a mouse model of nephrotoxic serum nephritis NTN by promoting the expression of BMP-7 in multipotent kidney side population cells Therefore, HDACs may contribute to renal fibrosis through multiple mechanisms.

Currently, individual HDAC family members in mediating fibroblast activation and tubular cell apoptosis remain to be identified. Experiments are underway to examine whether any of those HDACs is responsible for renal interstitial fibroblast activation. In summary, we demonstrated for the first time that blockade of HDACs inhibits the activation of renal interstitial fibroblasts in vitro and in vivo.

Currently, more than a dozen of HDAC inhibitors are in clinical trials for treatment of malignancies of almost all organ origins 26 , 35 , and a HDAC inhibitor, suberoylanilide hydroxamic acid, is already in clinical use for the treatment of cutaneous lymphoma Thus it will be interesting to further assess the clinical value of HDAC inhibition as therapeutics for renal diseases associated with fibroblast activation, especially, for CKD in the future. National Center for Biotechnology Information , U.

Am J Physiol Renal Physiol. Published online Jul Eugene Chin. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Address for reprint requests and other correspondence: S.

Zhuang, Brown Univ. Received May 21; Accepted Jul This article has been cited by other articles in PMC. Abstract Activation of renal interstitial fibroblasts is critically involved in the development of tubulointerstitial fibrosis in chronic kidney diseases.

Keywords: trichostatin A, histone deacetylase, renal interstitial fibroblasts, unilateral ureteral obstruction, STAT3. Cell culture. Nucleosome extraction. Western blot analysis. Immunochemical analysis. Interstitial fibrosis evaluated by sirius red staining.

Statistical analysis. Open in a separate window. TSA decreases renal interstitial fibrosis. Restoration of CREB function ameliorates cisplatin cytotoxicity in renal tubular cells. Obstructive nephropathy: insights from genetically engineered animals.

Isoform-selective histone deacetylase inhibitors. Histological, immunohistochemical and biological data in assessing interstitial fibrosis in patients with chronic glomerulonephritis. Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity. Chen Z, Han ZC. STAT3: a critical transcription activator in angiogenesis. Morphometry of interstitial fibrosis. Induction of apoptosis in renal tubular cells by histone deacetylase inhibitors, a family of anticancer agents.

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