Cutaneous exposure to lewisite causes acute kidney injury by invoking DNA damage and autophagic response
Cutaneous exposure to lewisite causes acute kidney injury by invoking DNA damage and autophagic response
复制标题
DOI：
10.1152/ajprenal.00277.2017
复制
发表时间：
2018-06-01
影响因子：
4.2
通讯作者：
Athar, Mohammad
中科院分区：
文献类型：
--
作者：
Srivastava, Ritesh K.;Traylor, Amie M.;Athar, Mohammad
路易氏剂（2-氯乙烯基二氯胂）是一种有机砷化学战剂，在第一次/第二次世界大战期间被开发和武器化。路易氏剂的储存仍然存在于世界许多地方，并对环境和人类健康构成潜在威胁。暴露于路易氏剂和类似的化学物质会引起强烈的皮肤炎症反应。然而，接触人群的发病率和死亡率不仅是皮肤损伤的结果，也是全身损伤的结果。在这里，我们提供的数据描绘急性肾损伤（阿基）的发病机制皮肤暴露于路易氏剂及其类似物氧化苯胂（PAO）在小鼠模型。两种药物均引起肾小管损伤，其特征为近端小管刷状缘丢失和肾小管细胞凋亡，伴有血清肌酐、中性粒细胞明胶酶相关脂质运载蛋白和肾损伤分子-1升高。有趣的是，路易氏剂暴露增强了肾脏中活性氧（ROS）的产生，并导致自噬和DNA损伤反应（DDR）信号传导途径的激活，分别增加了beclin-1、自噬相关基因7和LC-3A/B-II的表达，并增加了γ-H2 A.X和检查点激酶1/2的磷酸化。在肾小管中检测到末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性细胞，沿着增强的促凋亡BAX/裂解的caspase-3和减少的抗凋亡BCL 2。通过皮肤应用抗氧化剂N-乙酰-L-半胱氨酸清除ROS减少路易氏体诱导的自噬和DNA损伤。总之，我们提供了局部暴露于路易氏剂导致阿基的证据。这些变化的分子机制涉及ROS依赖的自噬激活和与诱导凋亡相关的DDR途径。
Lewisite (2-chlorovinyldichloroarsine) is an organic arsenical chemical warfare agent that was developed and weaponized during World Wars I/II. Stockpiles of lewisite still exist in many parts of the world and pose potential environmental and human health threat. Exposure to lewisite and similar chemicals causes intense cutaneous inflammatory response. However, morbidity and mortality in the exposed population is not only the result of cutaneous damage but is also a result of systemic injury. Here, we provide data delineating the pathogenesis of acute kidney injury (AKI) following cutaneous exposure to lewisite and its analog phenylarsine oxide (PAO) in a murine model. Both agents caused renal tubular injury, characterized by loss of brush border in proximal tubules and tubular cell apoptosis accompanied by increases in serum creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Interestingly, lewisite exposure enhanced production of reactive oxygen species (ROS) in the kidney and resulted in the activation of autophagic and DNA damage response (DDR) signaling pathways with increased expression of beclin-1, autophagy-related gene 7, and LC-3A/B-II and increased phosphorylation of gamma-H2A.X and checkpoint kinase 1/2, respectively. Terminal deoxyribonucleotide-transferase-mediated dUTP nick-end labeling-positive cells were detected in renal tubules along with enhanced proapoptotic BAX/cleaved caspase-3 and reduced antiapoptotic BCL2. Scavenging ROS by cutaneous postexposure application of the antioxidant N-acetyl-L-cysteine reduced lewisite-induced autophagy and DNA damage. In summary, we provide evidence that topical exposure to lewisite causes AKI. The molecular mechanism underlying these changes involves ROS-dependent activation of autophagy and DDR pathway associated with the induction of apoptosis.