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


METHODS
Male Wistar rats at 8 weeks of age were either administered with: a) lipopolysaccharide (LPS) only for three hours (3 h) or b) LPS, followed by continuous administration of landiolol for 3 h; c) third group was only treated with vehicle.


RESULTS
At 3 h 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 3 h normalized elevated serum markers of renal injury and up-regulated levels of renal HIF-1α-ET-1 system with normalization of TNF-α.


CONCLUSIONS
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.
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: s0911688@u.tsukuba.ac.jp.
Yoshiyasu
Y
Ogura
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: jsubrina@gmail.com.
Subrina
S
Jesmin
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: yamaguchi@ipu.ac.jp.
Naoto
N
Yamaguchi
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: s1321258@u.tsukuba.ac.jp.
Masami
M
Oki
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: nokeshimojo@yahoo.co.jp.
Nobutake
N
Shimojo
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: majedul1987@yahoo.com.
Md Majedul
MM
Islam
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: sarminr16@gmail.com.
Tanzila
T
Khatun
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: megmagmeggen@yahoo.co.jp.
Junko
J
Kamiyama
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: gongehead@yahoo.co.jp.
Hideaki
H
Sakuramoto
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: hagiya916@yahoo.co.jp.
Keiichi
K
Hagiya
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: kawano_s@md.tsukuba.ac.jp.
Satoru
S
Kawano
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for Health Science, Ibaraki Prefectural University, Ami, Ibaraki, Japan. Electronic address: mizutani@md.tsukuba.ac.jp.
Taro
T
Mizutani
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism*; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides; D008297:Male; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D015415:Biomarkers; D019332:Endothelin-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009025:Morpholines; D012333:RNA, Messenger; C036757:lipopolysaccharide B; C077049:landiolol; D014508:Urea
Endothelin; Endotoxemia; Kidney; Landiolol hydrochloride; Rat model