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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Protective role of HO-1 against acute kidney injury caused by cutaneous exposure to arsenicals.

Authors: Srivastava, Ritesh K; Muzaffar, Suhail; Khan, Jasim; Traylor, Amie M; Zmijewski, Jaroslaw W; Curtis, Lisa M; George, James F; Ahmad, Aftab; Antony, Veena B; Agarwal, Anupam; Athar, Mohammad

Published In Ann N Y Acad Sci, (2020 Nov)

Abstract: Lewisite and many other similar arsenicals are warfare vesicants developed and weaponized for use in World Wars I and II. These chemicals, when exposed to the skin and other epithelial tissues, cause rapid severe inflammation and systemic damage. Here, we show that topically applied arsenicals in a murine model produce significant acute kidney injury (AKI), as determined by an increase in the AKI biomarkers NGAL and KIM-1. An increase in reactive oxygen species and ER stress proteins, such as ATF4 and CHOP, correlated with the induction of these AKI biomarkers. Also, TUNEL staining of CHOP-positive renal tubular cells suggests CHOP mediates apoptosis in these cells. A systemic inflammatory response characterized by a significant elevation in inflammatory mediators, such as IL-6, IFN-α, and COX-2, in the kidney could be the underlying cause of AKI. The mechanism of arsenical-mediated inflammation involves activation of AMPK/Nrf2 signaling pathways, which regulate heme oxygenase-1 (HO-1). Indeed, HO-1 induction with cobalt protoporphyrin (CoPP) treatment in arsenical-treated HEK293 cells afforded cytoprotection by attenuating CHOP-associated apoptosis and cytokine mRNA levels. These results demonstrate that topical exposure to arsenicals causes AKI and that HO-1 activation may serve a protective role in this setting.

PubMed ID: 32885420 Exiting the NIEHS site

MeSH Terms: AMP-Activated Protein Kinases/metabolism; Activating Transcription Factor 4/metabolism; Acute Kidney Injury*/chemically induced; Acute Kidney Injury*/metabolism; Acute Kidney Injury*/pathology; Acute Kidney Injury*/prevention & control; Animals; Apoptosis/drug effects*; Arsenicals*; Biomarkers/metabolism; Chemical Warfare Agents/poisoning*; Cyclooxygenase 2/metabolism; Enzyme Activation/drug effects; HEK293 Cells; Heme Oxygenase-1/metabolism*; Hepatitis A Virus Cellular Receptor 1/metabolism; Humans; Interleukin-6/metabolism; Membrane Proteins/metabolism*; Mice; Mice, Hairless; NF-E2-Related Factor 2/metabolism; Signal Transduction/drug effects*; Transcription Factor CHOP/metabolism

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