Martinez-Moreno Julio M, Fontecha-Barriuso Miguel, Martín-Sánchez Diego, Sánchez-Niño Maria D, Ruiz-Ortega Marta, Sanz Ana B, Ortiz Alberto
Research Institute-Fundacion Jimenez Diaz, Autonomous University of Madrid (UAM), Madrid, Spain.
Red de Investigación Renal (REDinREN), Madrid, Spain.
Front Pharmacol. 2020 Apr 3;11:393. doi: 10.3389/fphar.2020.00393. eCollection 2020.
Acute kidney injury (AKI) and chronic kidney disease (CKD) are the most severe consequences of kidney injury. They are interconnected syndromes as CKD predisposes to AKI and AKI may accelerate CKD progression. Despite their growing impact on the global burden of disease, there is no satisfactory treatment for AKI and current therapeutic approaches to CKD remain suboptimal. Recent research has focused on the therapeutic target potential of epigenetic regulation of gene expression, including non-coding RNAs and the covalent modifications of histones and DNA. Indeed, several drugs targeting histone modifications are in clinical use or undergoing clinical trials. Acyl-lysine histone modifications (e.g. methylation, acetylation, and crotonylation) have modulated experimental kidney injury. Most recently, increased histone lysine crotonylation (Kcr) was observed during experimental AKI and could be reproduced in cultured tubular cells exposed to inflammatory stress triggered by the cytokine TWEAK. The degree of kidney histone crotonylation was modulated by crotonate availability and crotonate supplementation protected from nephrotoxic AKI. We now review the functional relevance of histone crotonylation in kidney disease and other pathophysiological contexts, as well as the implications for the development of novel therapeutic approaches. These studies provide insights into the overall role of histone crotonylation in health and disease.
急性肾损伤（AKI）和慢性肾脏病（CKD）是肾损伤最严重的后果。它们是相互关联的综合征，因为CKD易引发AKI，而AKI可能加速CKD的进展。尽管它们对全球疾病负担的影响日益增大，但目前尚无令人满意的AKI治疗方法，且CKD的现有治疗方法仍不尽人意。最近的研究集中在基因表达表观遗传调控的治疗靶点潜力上，包括非编码RNA以及组蛋白和DNA的共价修饰。事实上，几种针对组蛋白修饰的药物正在临床使用或正在进行临床试验。酰基赖氨酸组蛋白修饰（如甲基化、乙酰化和巴豆酰化）已调节实验性肾损伤。最近，在实验性AKI期间观察到组蛋白赖氨酸巴豆酰化（Kcr）增加，并且在暴露于细胞因子TWEAK触发的炎症应激的培养肾小管细胞中也能重现。组蛋白巴豆酰化程度受巴豆酸盐可用性调节，补充巴豆酸盐可预防肾毒性AKI。我们现在综述组蛋白巴豆酰化在肾脏疾病和其他病理生理背景下的功能相关性，以及对新型治疗方法开发的意义。这些研究为组蛋白巴豆酰化在健康和疾病中的整体作用提供了见解。
