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      Inhibition of HDAC6 activity in kidney diseases: a new perspective

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          Abstract

          Histone deacetylase 6 (HDAC6), a cytoplasmic enzyme that plays important roles in many biological processes, is one isoform of a family of HDAC enzymes that catalyse the removal of functional acetyl groups from proteins. HDAC6 stands out from the other members of this family because it almost exclusively deacetylates cytoplasmic proteins and exerts deacetylation-independent effects, which has led to the successful development of relatively isoform-specific inhibitors of its enzymatic action. Numerous studies have recently demonstrated that HDAC6 expression and activity are increased in kidney disease, such as autosomal dominant polycystic kidney disease (ADPKD), renal fibrosis, and acute kidney injury (AKI), among others. Moreover, HDAC6 inhibitors have been investigated for use in treating these diseases. In fact, HDAC6 inhibitors effectively limit the progression of kidney diseases, suggesting that targeting HDAC6 may provide a novel treatment approach. However, the primary challenge in developing HDAC6-targeted therapies is understanding how the renoprotective effect of NDAC6 inhibitors can be selectively harnessed. Here, we discuss the unique function of HDAC6 and recapitulate the alluring potential of its inhibitors in kidney diseases.

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          Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model

          Transient, genetic elimination of a specialized group of cells called plasmacytoid dendritic cells (pDCs) reverses many features of lupus in mice. Disease reduction was attributed in part to decreased expression of inflammatory molecules called interferons, which are produced primarily by pDCs.
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            Three proteins define a class of human histone deacetylases related to yeast Hda1p.

            Gene expression is in part controlled by chromatin remodeling factors and the acetylation state of nucleosomal histones. The latter process is regulated by histone acetyltransferases and histone deacetylases (HDACs). Previously, three human and five yeast HDAC enzymes had been identified. These can be categorized into two classes: the first class represented by yeast Rpd3-like proteins and the second by yeast Hda1-like proteins. Human HDAC1, HDAC2, and HDAC3 proteins are members of the first class, whereas no class II human HDAC proteins had been identified. The amino acid sequence of Hda1p was used to search the GenBank/expressed sequence tag databases to identify partial sequences from three putative class II human HDAC proteins. The corresponding full-length cDNAs were cloned and defined as HDAC4, HDAC5, and HDAC6. These proteins possess certain features present in the conserved catalytic domains of class I human HDACs, but also contain additional sequence domains. Interestingly, HDAC6 contains an internal duplication of two catalytic domains, which appear to function independently of each other. These class II HDAC proteins have differential mRNA expression in human tissues and possess in vitro HDAC activity that is inhibited by trichostatin A. Coimmunoprecipitation experiments indicate that these HDAC proteins are not components of the previously identified HDAC1 and HDAC2 NRD and mSin3A complexes. However, HDAC4 and HDAC5 associate with HDAC3 in vivo. This finding suggests that the human class II HDAC enzymes may function in cellular processes distinct from those of HDAC1 and HDAC2.
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              Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus

              Genetic impairment of plasmacytoid dendritic cells ameliorates autoantibody production and symptoms of SLE in mice.
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                Author and article information

                Contributors
                xiangdongfang818@sina.com
                yangliping2018@sina.com
                Journal
                Mol Med
                Mol. Med
                Molecular Medicine
                BioMed Central (London )
                1076-1551
                1528-3658
                26 June 2018
                26 June 2018
                2018
                : 24
                : 33
                Affiliations
                [1 ]GRID grid.412455.3, Department of Nephrology, , The Second Affiliated Hospital of Nanchang University, ; Nanchang, 330006 Jiangxi China
                [2 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Endocrinology, , The Affiliated Tongji Hospital of Huazhong University of Science and Technology, ; Wuhan, 430000 Hubei China
                [3 ]GRID grid.452437.3, Department of Intensive Care Unit, , The First Affiliated Hospital of Gannan Medical University, ; Ganzhou, 341000 Jiangxi China
                [4 ]ISNI 0000 0004 1763 3891, GRID grid.452533.6, Department of Breast, , Jiangxi Cancer Hospital, ; Nanchang, 330006 Jiangxi China
                [5 ]Nanchang, People’s Republic of China
                Article
                27
                10.1186/s10020-018-0027-4
                6019784
                30134806
                c2503693-ab06-4504-a69c-d841a6bec719
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 27 March 2018
                : 16 May 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81760130
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                histone deacetylase 6,autosomal dominant polycystic kidney disease,renal fibrosis,lupus nephritis,acute kidney injury

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