Ebselen Alleviates Sepsis-Induced Acute Kidney Injury by Regulating Endoplasmic Reticulum Stress, Apoptosis, and Oxidative Stress.

Abstract

Acute kidney injury (AKI) is one of the most serious complications of sepsis, with substantial morbidity and mortality, and no effective treatment exists. Ebselen is of pharmacological significance in the treatment and prevention of a variety of human diseases, such as cancer and cardiovascular disorders. Nevertheless, the role of Ebselen in the pathogenesis of sepsis-induced AKI remains unknown. Therefore, we aimed to elucidate the impact of Ebselen, an active seleno-organic compound, on AKI induced by lipopolysaccharide (LPS) and the associated molecular mechanisms, including endoplasmic reticulum (ER) stress, apoptosis, and oxidative stress. We established the sepsis-induced AKI rat model by injecting 5 mg/kg of LPS intraperitoneally. The rats were given Ebselen (5 and 10 mg/kg, orally) before receiving the LPS injection. Ebselen treatment alleviated renal tubular injury and reduced the levels of blood urea nitrogen (BUN) and creatinine (CREA) in LPS-induced sepsis model. Immunohistochemical and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) analyses revealed that Ebselen reduced caspase-3 expressions and apoptotic cells triggered by LPS in kidney tissues. LPS-induced sepsis caused ER stress, and Ebselen treatment alleviated the ER stress by regulating eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3) and GRP78 in kidney tissue, as well as activating transcription factor 4 (ATF4) and activating transcription factor 6 (ATF6) in serum. Ebselen decreased malondialdehyde (MDA) levels induced by LPS. Ebselen alleviated LPS-induced oxidative stress by modulating MDA and superoxide dismutase (SOD) levels in kidney tissues and SOD, glutathione peroxidase (GPx) and serum total antioxidant status (TAS) levels in serum. In conclusion, we report for the time that Ebselen might alleviate sepsis-induced AKI through the regulation of ER stress apoptosis and oxidative stress.