Dreval Kostiantyn, de Conti Aline, Furuya Shinji, Beland Frederick A, Rusyn Ivan, Pogribny Igor P
Division of Biochemical Toxicology, National Center for Toxicological Research 3900 NCTR Rd, Jefferson, AR 72079, USA.
Department of Veterinary Integrative Biosciences, Texas A&M University, 4458 TAMU, College Station, TX 77843, USA.
Toxicology. 2017 Jun 1;384:40-49. doi: 10.1016/j.tox.2017.03.004. Epub 2017 Mar 8.
Excessive alcohol consumption has a significant impact on human health and is a major public health problem worldwide. One of the consequences of long-term excessive alcohol consumption is cellular injury in almost all organs and tissues, with acute kidney injury (AKI) being one of the most common pathological manifestations. In the present study, using a mouse model of alcoholic liver fibrosis-associated AKI induced by a combined treatment with carbon tetrachloride (CCl) and ethanol and resembling pathological features of AKI in human alcoholic liver fibrosis, we demonstrate alterations in histone modifications in the kidneys and, importantly, in the promoter region of the over-expressed SRY (sex determining region Y)-box 9 (Sox9) gene. The level of SOX9 protein in the kidneys of AKI-mice is reduced and correlates inversely with increased expression of microRNA miR-1247. Mechanistically, the over-expression of miR-1247 is associated with a markedly increase in histone H3 lysine 4 trimethylation in the upstream region of the Mir1247 gene. The results of the present study demonstrate a functional role of epigenetic mechanisms in AKI and indicate the importance of correcting the epigenetic dysregulation for proper renal tubule maintenance and repair.
过度饮酒对人类健康有重大影响，是全球主要的公共卫生问题之一。长期过度饮酒的后果之一是几乎所有器官和组织都会出现细胞损伤，急性肾损伤（AKI）是最常见的病理表现之一。在本研究中，我们使用由四氯化碳（CCl）和乙醇联合处理诱导的酒精性肝纤维化相关AKI小鼠模型，该模型类似于人类酒精性肝纤维化中AKI的病理特征，我们证明了肾脏中组蛋白修饰的改变，重要的是，在过表达的性别决定区Y盒9（Sox9）基因的启动子区域也有改变。AKI小鼠肾脏中SOX9蛋白水平降低，且与微小RNA miR-1247表达增加呈负相关。从机制上讲，miR-1247的过表达与Mir1247基因上游区域组蛋白H3赖氨酸4三甲基化的显著增加有关。本研究结果证明了表观遗传机制在AKI中的功能作用，并表明纠正表观遗传失调对于肾小管的正常维持和修复至关重要。
