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

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.

• Authors: Ritesh K Srivastava, Suhail Muzaffar, Jasim Khan, Amie M Traylor, Jaroslaw W Zmijewski, Lisa M Curtis, James F George, Aftab Ahmad, Veena B Antony, Anupam Agarwal, Mohammad Athar
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 1480 Issue 1 Pg. 155-169 (11 2020) ISSN: 1749-6632 [Electronic] United States
• PMID: 32885420 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2020 New York Academy of Sciences.

Chemical References

• Arsenicals
• Atf4 protein, mouse
• Biomarkers
• Chemical Warfare Agents
• Ddit3 protein, mouse
• Havcr1 protein, mouse
• Hepatitis A Virus Cellular Receptor 1
• Interleukin-6
• Membrane Proteins
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• interleukin-6, mouse
• lewisite
• Activating Transcription Factor 4
• Transcription Factor CHOP
• Heme Oxygenase-1
• Hmox1 protein, mouse
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Activating Transcription Factor 4 (metabolism)
• Acute Kidney Injury (chemically induced, metabolism, pathology, 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)