Cutaneous exposure to lewisite causes acute kidney injury by invoking DNA damage and autophagic response
Autor: | Veena B. Antony, Lingling Guo, Amie M. Traylor, Mohammad Athar, Ritesh K. Srivastava, Wenguang Feng, Trenton R. Schoeb, Changzhao Li, Anupam Agarwal |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine Lewisite Physiology DNA damage Skin Absorption 030232 urology & nephrology Apoptosis Pharmacology Kidney Antioxidants Arsenicals 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Autophagy medicine Animals Humans Chemical Warfare Agents Deoxyribonucleic acid damage chemistry.chemical_classification Mice Hairless Reactive oxygen species Acute kidney injury Acute Kidney Injury medicine.disease Oxidative Stress HEK293 Cells 030104 developmental biology Systemic toxicity chemistry Cytokines Female Reactive Oxygen Species DNA Damage Signal Transduction Research Article |
Zdroj: | American Journal of Physiology-Renal Physiology. 314:F1166-F1176 |
ISSN: | 1522-1466 1931-857X |
Popis: | 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 γ-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. |
Databáze: | OpenAIRE |
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