Epigenetic therapeutics attenuate kidney injury and fibrosis by restoring the expression of epigenetically reprogrammed fibrogenic genes and signaling pathways

IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2025-01-01 DOI:10.1016/j.ejps.2024.106977
Narayan Acharya , Ramji Kandel , Priti Roy , Irfan Warraich , Kamaleshwar P Singh
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Abstract

Kidney fibrosis is a commonly observed pathological condition during development of chronic kidney disease. Therapeutic options currently available are effective only in slowing the progression of kidney fibrosis and there is no cure for this disease. Aberrant expression and excessive accumulation of extracellular matrix (ECM) proteins in the peritubular space is a characteristic pathological feature of fibrotic kidney. However, the molecular basis of aberrant regulation of fibrotic genes in kidneys is not clear. In this context, this study aimed to evaluate the role of epigenetic reprogramming in kidney fibrosis. Folic acid (FA)-induced acute kidney injury (AKI) and kidney fibrosis in mice as an in vivo model and long-term arsenic or FA-exposed fibrogenic HK-2 cells as an in vitro model were used to evaluate the role of DNA methylation and histone modifications in fibrosis. DNA demethylating agent 5aza2 deoxycytidine (5-aza-2-dC) and histone deacetylase inhibitor Trichostatin A (TSA) were used to treat FA-injected mice. Results of histopathological and immunofluorescence staining of kidney tissue, serum albumin- creatinine levels, body weight, and gene expression analysis revealed significant protective effects of 5-aza-2-dC and TSA in FA-induced AKI and fibrosis. Insignificant change in the expression of N-cadherin whereas a significant decrease in E-cadherin as well as an increase in the expression of Vimentin and α-SMA suggest partial EMT associated with fibrosis. Aberrant expression of epithelial-mesenchymal-transition (EMT) and ECM-regulators (MMP2, Smad7, and TIMP3) as well as fibrogenic signaling pathways (Notch, TGF-beta, and Wnt signaling), and their restoration by 5-aza-2-dC and TSA treatments suggest epigenetic reprogramming of these genes and signaling pathways during FA-induced fibrosis. In summary, this study provides new information on the role of epigenetic reprogramming of fibrogenic genes and signaling pathways during the development of kidney fibrosis. Attenuation of fibrosis after 5-aza-2-dC and TSA treatments suggest the promise of these epigenetic-based therapeutics in the clinical management of this disease.

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表观遗传疗法通过恢复表观遗传重编程的纤维化基因和信号通路的表达来减轻肾损伤和纤维化。
肾纤维化是慢性肾脏疾病发展过程中常见的病理状态。目前可用的治疗方案仅在减缓肾纤维化的进展方面有效,而且这种疾病无法治愈。小管周围细胞外基质(ECM)蛋白的异常表达和过度积累是纤维化肾的一个特征性病理特征。然而,肾脏纤维化基因异常调控的分子基础尚不清楚。在此背景下,本研究旨在评估表观遗传重编程在肾纤维化中的作用。采用叶酸(FA)诱导的小鼠急性肾损伤(AKI)和肾纤维化作为体内模型,并采用长期砷或FA暴露的纤维化性HK-2细胞作为体外模型来评估DNA甲基化和组蛋白修饰在纤维化中的作用。用DNA去甲基化剂5aza2脱氧胞苷(5-aza-2-dC)和组蛋白去乙酰化酶抑制剂Trichostatin A (TSA)治疗fa注射小鼠。肾组织病理和免疫荧光染色、血清白蛋白-肌酐水平、体重和基因表达分析结果显示,5-aza-2-dC和TSA对fa诱导的AKI和纤维化具有显著的保护作用。N-cadherin的表达变化不显著,而E-cadherin的表达显著降低,Vimentin和α-SMA的表达增加,提示部分EMT与纤维化有关。上皮-间质转化(EMT)和ecm调节因子(MMP2、Smad7和TIMP3)以及纤维化信号通路(Notch、tgf - β和Wnt信号通路)的异常表达,以及5-aza-2-dC和TSA治疗对它们的恢复表明,在fa诱导的纤维化过程中,这些基因和信号通路发生了表观遗传重编程。总之,本研究为纤维化基因的表观遗传重编程和信号通路在肾纤维化发展过程中的作用提供了新的信息。5-aza-2-dC和TSA治疗后纤维化的衰减表明这些基于表观遗传学的治疗方法在该疾病的临床管理中有希望。
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来源期刊
CiteScore
9.60
自引率
2.20%
发文量
248
审稿时长
50 days
期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
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