Acharya Narayan, Kandel Ramji, Roy Priti, Warraich Irfan, Singh Kamaleshwar P
Department of Environmental Toxicology, Texas Tech University, Lubbock, TX 79409, United States.
Department of Pathology, Texas Tech University Health Science Center, Lubbock, TX 79430, United States.
Eur J Pharm Sci. 2025 Jan 1;204:106977. doi: 10.1016/j.ejps.2024.106977. Epub 2024 Nov 29.
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.
肾纤维化是慢性肾脏病发展过程中常见的病理状态。目前可用的治疗方法仅能有效减缓肾纤维化的进展，尚无治愈该病的方法。肾小管周围间隙中细胞外基质（ECM）蛋白的异常表达和过度积累是纤维化肾脏的特征性病理特征。然而，肾脏中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，以及长期暴露于砷或FA的致纤维化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。使用DNA去甲基化剂5-氮杂-2'-脱氧胞苷（5-aza-2-dC）和组蛋白去乙酰化酶抑制剂曲古抑菌素A（TSA）治疗注射FA的小鼠。肾脏组织的组织病理学和免疫荧光染色结果、血清白蛋白-肌酐水平、体重及基因表达分析显示，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-钙黏蛋白表达无显著变化，而E-钙黏蛋白显著减少，波形蛋白和α-平滑肌肌动蛋白表达增加，提示与纤维化相关的部分上皮-间质转化（EMT）。上皮-间质转化（EMT）和ECM调节因子（基质金属蛋白酶2、Smad7和金属蛋白酶组织抑制因子3）以及纤维化信号通路（Notch、转化生长因子-β和Wnt信号通路）的异常表达，以及5-aza-2-dC和TSA处理对其的恢复作用，提示在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，本研究为肾纤维化发展过程中纤维化基因和信号通路的表观遗传重编程作用提供了新信息。5-aza-2-dC和TSA处理后纤维化减轻，提示这些基于表观遗传学的治疗方法在该病临床管理中的应用前景。
