Potential amelioration of upregulated renal HIF-1alpha–endothelin-1 system by landiolol hydrochloride in a rat model of endotoxemia

• Published in: Life sciences (1973) Vol. 118; no. 2; pp. 347 - 356
• Main Authors: Ogura, Yoshiyasu, Jesmin, Subrina, Yamaguchi, Naoto, Oki, Masami, Shimojo, Nobutake, Islam, Md. Majedul, Khatun, Tanzila, Kamiyama, Junko, Sakuramoto, Hideaki, Hagiya, Keiichi, Kawano, Satoru, Mizutani, Taro
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 24.11.2014
• Subjects: Animals; Biomarkers - blood; Blood Gas Analysis; Blood Pressure - drug effects; Disease Models, Animal; Endothelin; Endothelin-1 - metabolism; Endotoxemia; Endotoxemia - blood; Endotoxemia - drug therapy; Endotoxemia - genetics; Endotoxemia - pathology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inflammation Mediators - metabolism; Kidney; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Landiolol hydrochloride; Lipopolysaccharides; Male; Morpholines - pharmacology; Morpholines - therapeutic use; Rat model; Rats, Wistar; RNA, Messenger - genetics; RNA, Messenger - metabolism; Up-Regulation - drug effects; Urea - analogs & derivatives; Urea - pharmacology; Urea - therapeutic use; Rat model; Endothelin; Landiolol hydrochloride; Kidney; Endotoxemia
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2014.05.007

Endothelin (ET)-1 is the best known potent vasoconstrictor and has been implicated in pathogenesis of sepsis-associated acute kidney injury (AKI) in human or lipopolysaccharide (LPS)-induced AKI in animal models. We have previously shown that ET-1 is highly up-regulated in renal tissues and in plasma after LPS administration. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting beta-blocker, can play an important role in ameliorating levels of LPS-induced up-regulation of renal HIF-1α–ET-1 system and inflammatory cytokines in a rat model of endotoxemia. Male Wistar rats at 8weeks of age were either administered with: a) lipopolysaccharide (LPS) only for three hours (3h) or b) LPS, followed by continuous administration of landiolol for 3h; c) third group was only treated with vehicle. At 3h after LPS administration there was: a) minimal injury in kidney tissues; b) circulatory levels of creatinine, blood urea nitrogen and NGAL increased and c) expression of inflammatory cytokines, such as TNF-α, IL-6 and iNOS increased at the level of both circulatory and renal tissues. In addition, LPS significantly induced renal expression of ET-1 and HIF-1α compared to control. Finally, treatment of LPS-administered rats with landiolol for 3h normalized elevated serum markers of renal injury and up-regulated levels of renal HIF-1α–ET-1 system with normalization of TNF-α. Taken together, these data led us to conclude that landiolol ameliorates the up-regulation of HIF-1α–ET-1 system in minimally morphologically-injured kidney and normalizes biomarkers of renal injury in early hours of endotoxemia of a rat model. [Display omitted]