title: Dexmedetomidine protects against renal ischemia and reperfusion injury by inhibiting the JAK/STAT signaling activation.
abstract: BACKGROUND
  The α2-adrenoreceptor agonist dexmedetomidine is known to provide renoprotection against ischemia and reperfusion (I/R) injury. However the underlying molecular mechanisms remain unclear. The purpose of this study was to investigate whether the Janus kinase and signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a role in dexmedetomidine's renoprotection.
  
  
  METHODS
  I/R model was induced by bilateral renal pedicle clamping for 45 min followed by 48 h of reperfusion in male Wistar rat. Sham laparotomy served as controls. Animals received dexmedetomidine (50 μg/kg, i.p.) in the absence or presence of atipamezole (250 μg/kg, i.p.), or vehicle (DMSO) in the absence or presence of selective JAK2 inhibitor tyrphostin AG490 (10 mg/kg, i.p.) before ischemia. Renal function, histology, apoptosis, expression of cleaved caspase 3 protein, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and phosphorylations of JAK2, STAT1 and STAT3 were assessed.
  
  
  RESULTS
  The animals treated with either dexmedetomidine or AG490 exhibited an improved renal functional recovery, attenuated histological lesions and reduced number of apoptotic tubular epithelial cells. Either dexmedetomidine or AG490 inhibited the phosphorylations of JAK2 and its downstream molecule STAT1 and STAT3, accompanied by down-regulation the expression of cleaved caspase 3, ICAM-1 and MCP-1 proteins, and significantly ameliorated renal I/R injury.
  
  
  CONCLUSIONS
  Dexmedetomidine protects kidney against I/R injury, at least in part, through its inhibitory effects on injury-induced activation of JAK/STAT signaling pathway. If our data can be extrapolated to clinical setting, then dexmedetomidine may therefore serve as a clinical strategy to treat/prevent perioperative renal I/R injury.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Si
authors.forename: Hongguang
authors.initials: H
authors.lastname: Bao
authors.forename: Liu
authors.initials: L
authors.lastname: Han
authors.forename: Hongwei
authors.initials: H
authors.lastname: Shi
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: Chenhui
authors.initials: C
authors.lastname: Liu
authors.forename: Jinsong
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Yang
authors.forename: Akbar
authors.initials: A
authors.lastname: Vohra
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D018932:Chemokine CCL2 / Q000097:blood; D020927:Dexmedetomidine / Q000494:pharmacology / Q000627:therapeutic use*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D053612:Janus Kinases / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control*; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D020011:Protective Agents; D050791:STAT Transcription Factors; D018799:Intercellular Adhesion Molecule-1; D020927:Dexmedetomidine; D053612:Janus Kinases; D053148:Caspase 3