Histone lysine crotonylation during acute kidney injury in mice.
Histone lysine crotonylation during acute kidney injury in mice.
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DOI：
10.1242/dmm.024455
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发表时间：
2016-06-01
影响因子：
4.3
通讯作者：
Sanz AB
中科院分区：
文献类型：
--
作者：
Ruiz-Andres O;Sanchez-Niño MD;Cannata-Ortiz P;Ruiz-Ortega M;Egido J;Ortiz A;Sanz AB
急性肾损伤（阿基）是一种潜在的致命疾病，除了肾功能替代外，没有其他治疗方法。翻译后组蛋白修饰调节基因表达和肾损伤。组蛋白巴豆酰化是近年来发现的一种翻译后修饰。我们假设组蛋白巴豆酰化可能调节肾损伤。在培养的小鼠近端肾小管细胞和叶酸或顺铂诱导的阿基小鼠的肾脏中研究了组蛋白巴豆酰化。在来自健康小鼠和人肾组织的肾小管细胞中观察到组蛋白赖氨酸巴豆酰化。阿基期间肾组织组蛋白巴豆酰化增加。这通过暴露于培养的肾小管细胞中的蛋白质TWEAK来再现。具体而言，ChIP-seq揭示了在TWEAK刺激的肾小管细胞和阿基肾组织中编码线粒体生物发生调节因子PGC-1α和sirtuin-3脱巴豆酸酶的基因处组蛋白巴豆酰化的富集。为了评估巴豆酰化在肾损伤中的作用，使用巴豆酸盐来增加体内培养的肾小管细胞或肾脏中的组蛋白巴豆酰化。巴豆酸增加培养的肾小管细胞和健康肾脏中PGC-1α和sirtuin-3的表达，降低CCL 2的表达。全身给予巴豆酸可防止实验性阿基，防止肾功能和肾脏PGC-1α和sirtuin-3水平降低以及CCL 2表达增加。这是第一次，我们已经确定的因素，如细胞应激和巴豆酸的可用性，增加组蛋白巴豆酰化在体内。总体而言，增加组蛋白巴豆酰化可能对阿基具有有益作用。这是第一次观察到在疾病状态下组蛋白巴豆酰化的治疗操作的体内潜力。总结：我们评估了表观遗传翻译后修饰组蛋白巴豆酰化在体内和细胞培养肾损伤过程中的作用，以及PGC-1α和SIRT 3在该过程中的参与。
Acute kidney injury (AKI) is a potentially lethal condition for which no therapy is available beyond replacement of renal function. Post-translational histone modifications modulate gene expression and kidney injury. Histone crotonylation is a recently described post-translational modification. We hypothesized that histone crotonylation might modulate kidney injury. Histone crotonylation was studied in cultured murine proximal tubular cells and in kidneys from mice with AKI induced by folic acid or cisplatin. Histone lysine crotonylation was observed in tubular cells from healthy murine and human kidney tissue. Kidney tissue histone crotonylation increased during AKI. This was reproduced by exposure to the protein TWEAK in cultured tubular cells. Specifically, ChIP-seq revealed enrichment of histone crotonylation at the genes encoding the mitochondrial biogenesis regulator PGC-1α and the sirtuin-3 decrotonylase in both TWEAK-stimulated tubular cells and in AKI kidney tissue. To assess the role of crotonylation in kidney injury, crotonate was used to increase histone crotonylation in cultured tubular cells or in the kidneys in vivo. Crotonate increased the expression of PGC-1α and sirtuin-3, and decreased CCL2 expression in cultured tubular cells and healthy kidneys. Systemic crotonate administration protected from experimental AKI, preventing the decrease in renal function and in kidney PGC-1α and sirtuin-3 levels as well as the increase in CCL2 expression. For the first time, we have identified factors such as cell stress and crotonate availability that increase histone crotonylation in vivo. Overall, increasing histone crotonylation might have a beneficial effect on AKI. This is the first observation of the in vivo potential of the therapeutic manipulation of histone crotonylation in a disease state. Summary: We have assessed the effect of the epigenetic post-translational modification histone crotonylation during kidney injury in vivo and in cell culture, and the involvement of PGC-1α and SIRT3 in the process.