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      Application of Histone Deacetylase Inhibitors in Renal Interstitial Fibrosis

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          Abstract

          Background: Renal interstitial fibrosis is characterized by the accumulation of extracellular matrix proteins, which is a common feature of chronic kidney diseases. Summary: Increasing evidence has shown the aberrant expression of histone deacetylases (HDACs) in the development and progression of renal fibrosis, suggesting the possibility of utilizing HDAC inhibitor (HDACi) as therapeutics for renal fibrosis. Recent studies have successfully demonstrated the antifibrotic effects of HDACis in various animal models, which are associated with multiple signaling pathways including TGF-β signaling, EGRF signaling, signal transducer and activator of transcription 3 pathway, and JNK/Notch2 signaling. This review will focus on the utilization of HDACi as antifibrotic agents and its relative molecular mechanisms. Key Messages: HDACis have shown promising results in antifibrotic therapy, and it is rational to anticipate that HDACis will improve clinical outcomes of renal fibrosis in the future.

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          Most cited references 73

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          Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis.

           J Yang,  Jie Liu (2001)
          Myofibroblast activation is a key event playing a critical role in the progression of chronic renal disease. Emerging evidence suggests that myofibroblasts can derive from tubular epithelial cells by an epithelial to mesenchymal transition (EMT); however, the details regarding the conversion between these two cell types are poorly understood. Here we dissect the key events during the process of EMT induced by transforming growth factor-beta1. Incubation of human tubular epithelial cells with transforming growth factor-beta1 induced de novo expression of alpha-smooth muscle actin, loss of epithelial marker E-cadherin, transformation of myofibroblastic morphology, and production of interstitial matrix. Time-course studies revealed that loss of E-cadherin was an early event that preceded other alterations during EMT. The transformed cells secreted a large amount of matrix metalloproteinase-2 that specifically degraded tubular basement membrane. They also exhibited an enhanced motility and invasive capacity. These alterations in epithelial phenotypes in vitro were essentially recapitulated in a mouse model of renal fibrosis induced by unilateral ureteral obstruction. Hence, these results indicate that tubular epithelial to myofibroblast transition is an orchestrated, highly regulated process involving four key steps including: 1) loss of epithelial cell adhesion, 2) de novo alpha-smooth muscle actin expression and actin reorganization, 3) disruption of tubular basement membrane, and 4) enhanced cell migration and invasion.
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            Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans.

            Chronic kidney disease is a leading cause of death in the United States. Tubulointerstitial fibrosis (TIF) is considered the final common pathway leading to end-stage renal disease (ESRD). Here, we used pharmacologic, genetic, in vivo, and in vitro experiments to show that activation of the Notch pathway in tubular epithelial cells (TECs) in patients and in mouse models of TIF plays a role in TIF development. Expression of Notch in renal TECs was found to be both necessary and sufficient for TIF development. Genetic deletion of the Notch pathway in TECs reduced renal fibrosis. Consistent with this, TEC-specific expression of active Notch1 caused rapid development of TIF. Pharmacologic inhibition of Notch activation using a γ-secretase inhibitor ameliorated TIF. In summary, our experiments establish that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development.
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              Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury.

               J. Yu,  Saehong Oh,  Hunjoo Ha (2009)
              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.
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                Author and article information

                Journal
                KDD
                KDD
                10.1159/issn.2296-9357
                Kidney Diseases
                S. Karger AG
                2296-9381
                2296-9357
                2020
                July 2020
                26 March 2020
                : 6
                : 4
                : 226-235
                Affiliations
                Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
                Author notes
                *Jinghong Zhao, MD, PhD, Department of Nephrology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Xinqiao Street 83, Shapingba, Chongqing 400037 (China), zhaojh@tmmu.edu.cn
                Article
                505295 Kidney Dis 2020;6:226–235
                10.1159/000505295
                © 2020 The Author(s) Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Tables: 2, Pages: 10
                Categories
                Review Article

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