Protective role of HO-1 against acute kidney injury caused by cutaneous exposure to arsenicals.
Ritesh K SrivastavaSuhail MuzaffarJasim KhanAmie M TraylorJaroslaw W ZmijewskiLisa M CurtisJames F GeorgeAftab AhmadVeena B AntonyAnupam AgarwalMohammad AtharPublished in: Annals of the New York Academy of Sciences (2020)
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.
Keyphrases
- acute kidney injury
- cell cycle arrest
- oxidative stress
- induced apoptosis
- pi k akt
- endoplasmic reticulum stress
- cardiac surgery
- diffuse large b cell lymphoma
- cell death
- signaling pathway
- inflammatory response
- reactive oxygen species
- cell proliferation
- gene expression
- immune response
- skeletal muscle
- epithelial mesenchymal transition
- early onset
- endothelial cells
- lipopolysaccharide induced
- flow cytometry