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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Renal tubule injury: a driving force toward chronic kidney disease.

Lin-Li Lv, Tao‐Tao Tang, Bi-Cheng Liu … (2018)

Renal tubules are the major component of the kidney and are vulnerable to a variety of injuries including hypoxia, proteinuria, toxins, metabolic disorders, and senescence. It has long been believed that tubules are the victim of injury. In this review, we shift this concept to renal tubules as a driving force in the progression of kidney diseases. In response to injury, tubular epithelial cells undergo changes and function as inflammatory and fibrogenic cells, with the consequent production of various bioactive molecules that drive interstitial inflammation and fibrosis. Innate immune-sensing receptors on the tubular epithelium also aggravate immune responses. Necroinflammation, an autoamplification loop between tubular cell death and interstitial inflammation, leads to the exacerbation of renal injury. Furthermore, tubular cells also play an active role in progressive renal injury via emerging mechanisms associated with a partial epithelial-mesenchymal transition, cell-cycle arrest at both G1/S and G2/M check points, and metabolic disorder. Thus, a better understanding the mechanisms by which tubular injury drives inflammation and fibrosis is necessary for the development of therapeutics to halt the progression of chronic kidney disease.

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

J Yang, Y. 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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Sirtuins in Renal Health and Disease.

Marina Morigi, Luca Perico, Ariela Benigni (2018)

Sirtuins belong to an evolutionarily conserved family of NAD+-dependent deacetylases that share multiple cellular functions related to proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammalians express seven sirtuins (SIRT1-7) that are localized in different subcellular compartments. Changes in sirtuin expression are critical in several diseases, including metabolic syndrome, diabetes, cancer, and aging. In the kidney, the most widely studied sirtuin is SIRT1, which exerts cytoprotective effects by inhibiting cell apoptosis, inflammation, and fibrosis together with SIRT3, a crucial metabolic sensor that regulates ATP generation and mitochondrial adaptive response to stress. Here, we provide an overview of the biologic effects of sirtuins and the molecular targets thereof regulating renal physiology. This review also details progress made in understanding the effect of sirtuins in the pathophysiology of chronic and acute kidney diseases, highlighting the key role of SIRT1, SIRT3, and now SIRT6 as potential therapeutic targets. In this context, the current pharmacologic approaches to enhancing the activity of SIRT1 and SIRT3 will be discussed.

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Journal

Journal ID (publisher-id): KDD

Journal ID (pmc): KDD

Journal ID (doi): 10.1159/issn.2296-9357

Title: Kidney Diseases

Publisher: S. Karger AG

ISSN (Print): 2296-9381

ISSN (Electronic): 2296-9357

Publication date Subscription-year: 2020

Publication date (Print): July 2020

Publication date (Electronic): 26 March 2020

Volume: 6

Issue: 4

Pages: 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

Publisher ID: 505295 Other ID: Kidney Dis 2020;6:226–235

DOI: 10.1159/000505295

PubMed ID: 32903948

SO-VID: ef3f7a4d-fc7c-41f6-bd32-40d7aefa1e72

License:

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.

History

Date received : 22 November 2019

Date accepted : 09 December 2019

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Figures: 1, Tables: 2, Pages: 10

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Application of Histone Deacetylase Inhibitors in Renal Interstitial Fibrosis

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Abstract

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Karger: Nephrology

Most cited references 73

Renal tubule injury: a driving force toward chronic kidney disease.

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

Sirtuins in Renal Health and Disease.

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Cited by 11

Most referenced authors 905