Cutaneous arsenical exposure induces distinct metabolic transcriptional alterations of kidney cells

Arsenicals are deadly chemical warfare agents which primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenicals are also known to cause acute kidney injury, a condition that contributes to arsenical-associated death due to the necessity of the kidney in maintaining whole-body fluid homeostasis. Because of the global health risk that arsenicals pose, a nuanced understanding of how arsenical exposure can lead to kidney injury is needed. Our study utilized a non-targeted transcriptional approach to evaluate the effects of cutaneous exposure to phenylarsine oxide, a common arsenical, in a murine model. Here, we demonstrate an upregulation of metabolic pathways such as fatty acid oxidation and PPAR-?? signaling within proximal tubule epithelial cells and endothelial cells in the kidney. We also reveal highly upregulated single genes related to metabolism and metabolic switching within these same cell types which may serve as future therapeutic targets. The ability of arsenicals to inhibit enzymes such as pyruvate dehydrogenase have been previously described in vitro. This along with our own data lead us to conclude that arsenical-induced acute kidney injury may be due to a metabolic impairment in proximal tubule and endothelial cells, and that appropriately ameliorating these metabolic effects may lead to the development of life-saving therapies. Overall design: C57/BL6J mice were administered phenylarsine oxide topically or ethanol as a vehicle control and kidneys were harvested six and twenty-four hours later for single nuclei RNA sequencing.

砷剂（arsenicals）是一类致命的化学战剂，主要通过引发全身性毛细血管液体渗漏与低血容量性休克导致死亡。现有研究表明，砷剂还可诱发急性肾损伤（acute kidney injury）；由于肾脏是维持全身体液稳态的核心器官，该病症也是砷剂相关死亡的重要诱因。鉴于砷剂存在全球性健康风险，亟需深入阐明砷剂暴露引发肾损伤的具体机制。本研究采用非靶向转录组学方法，在小鼠模型中评估皮肤暴露于常见砷剂氧化苯胂（phenylarsine oxide）所产生的生物学效应。研究结果显示，肾脏近端小管上皮细胞与内皮细胞内的脂肪酸氧化、PPAR-??信号通路等代谢通路出现显著上调；同时在上述两类细胞中，与代谢及代谢转换相关的单基因亦呈现高度上调，这些基因有望成为未来的治疗靶点。此前已有体外研究证实砷剂可抑制丙酮酸脱氢酶等酶类的活性，结合本研究数据，我们认为砷剂诱导的急性肾损伤可能源于近端小管细胞与内皮细胞的代谢功能受损，而针对性改善这类代谢异常或可开发出挽救生命的治疗策略。

整体实验设计：对C57/BL6J小鼠经皮肤给予氧化苯胂，或以乙醇作为溶剂对照，分别在给药后6小时与24小时采集肾脏组织，进行单细胞核RNA测序（single nuclei RNA sequencing）。