title: Dexmedetomidine provides renoprotection against ischemia-reperfusion injury in mice.
abstract: BACKGROUND
  Acute kidney injury following surgery incurs significant mortality with no proven preventative therapy. We investigated whether the α2 adrenoceptor agonist dexmedetomidine (Dex) provides protection against ischemia-reperfusion induced kidney injury in vitro and in vivo.
  
  
  METHODS
  In vitro, a stabilised cell line of human kidney proximal tubular cells (HK2) was exposed to culture medium deprived of oxygen and glucose. Dex decreased HK2 cell death in a dose-dependent manner, an effect attenuated by the α2 adrenoceptor antagonist atipamezole, and likely transduced by phosphatidylinositol 3-kinase (PI3K-Akt) signaling. In vivo C57BL/6J mice received Dex (25 μg/kg, intraperitoneal (i.p.)) 30 minutes before or after either bilateral renal pedicle clamping for 25 minutes or right renal pedicle clamping for 40 minutes and left nephrectomy.
  
  
  RESULTS
  Pre- or post-treatment with Dex provided cytoprotection, improved tubular architecture and function following renal ischemia. Consistent with this cytoprotection, dexmedetomidine reduced plasma high-mobility group protein B1 (HMGB-1) elevation when given prior to or after kidney ischemia-reperfusion; pretreatment also decreased toll-like receptor 4 (TLR4) expression in tubular cells. Dex treatment provided long-term functional renoprotection, and even increased survival following nephrectomy.
  
  
  CONCLUSIONS
  Our data suggest that Dex likely activates cell survival signal pAKT via α2 adrenoceptors to reduce cell death and HMGB1 release and subsequently inhibits TLR4 signaling to provide reno-protection.
authors.affiliation: Department of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Campus, 369 Fulham Rd, London SW10 9NH, UK.
authors.forename: Jianteng
authors.initials: J
authors.lastname: Gu
authors.forename: Pamela
authors.initials: P
authors.lastname: Sun
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhao
authors.forename: Helena R
authors.initials: HR
authors.lastname: Watts
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sanders
authors.forename: Niccolo
authors.initials: N
authors.lastname: Terrando
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Xia
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D002460:Cell Line; D020927:Dexmedetomidine / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*
chemical_list: D020011:Protective Agents; D020927:Dexmedetomidine