Cutaneous Arsenical Exposure Induces Distinct Metabolic Transcriptional Alterations of Kidney Cells

Abstract

Arsenicals are deadly chemical warfare agents which primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is 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. We 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 identified an upregulation of metabolic pathways such as fatty acid oxidation, fatty acid biosynthesis, and PPAR-𝛼 signaling in proximal tubule epithelial cell and endothelial cell clusters. We also revealed highly upregulated genes such as Zbtb16, Cyp4a14, and Pdk4, which are involved in metabolism and metabolic switching and 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 arsenicalinduced acute kidney injury may be due to a metabolic impairment in proximal tubule and endothelial cells, and that ameliorating these metabolic effects may lead to the development of life-saving therapies.

Progress and Challenges in Developing Medical Countermeasures for Chemical, Biological, Radiological, and Nuclear Threat Agents

“…While antidotes like British anti-Lewisite exist, their limited application and potential toxic side effects underscore the urgent need for more effective treatments against arsenical exposure. George and colleagues explored the transcriptomic effects of cutaneous exposure to PAO, a common arsenical, on the kidneys of mice ( Moore et al, 2024 ). They found that PAO exposure upregulates metabolic pathways, such as fatty acid oxidation and PPAR-α signaling, and genes in proximal tubule epithelial cells and endothelial cells.…”

Special Section on Medical Countermeasures, From Bench to Battlefield: Translating Experimental Therapies for Effective Combat Against Chemical Threats–Editorial

“…CoN4[14] is presented as a promising antidote for cyanide and azide poisoning (Pearce et al, 2024a). Studying metabolic alterations caused by arsenical exposure identifies potential new targets for treating arsenical-induced kidney injury (Moore et al, 2024).…”