title: TGF-beta1 release by volatile anesthetics mediates protection against renal proximal tubule cell necrosis.
abstract: OBJECTIVE
  We have previously demonstrated that clinically utilized volatile anesthetics protect against renal ischemia reperfusion injury in rats in vivo and reduce necrosis in vitro via activation of ERK and Akt and by upregulating HSP70. In this study, we further deciphered the upstream cellular signaling mechanism(s) of volatile anesthetic-mediated antinecrotic effects in vitro. We hypothesized that volatile anesthetics perturb the structure of the plasma membrane lipid bilayer, causing externalization of phosphatidylserine (PS) to the outer surface on renal tubule cells leading to the increased generation of transforming growth factor-beta1 (TGF-beta1), a cytokine with antinecrotic properties.
  
  
  RESULTS
  In human proximal tubule (HK-2) cell culture, 16-hour exposure to volatile anesthetics (isoflurane, halothane, sevoflurane) caused membrane externalization of PS detected by positive annexin-V staining and increased the release of TGF-beta1 into the cell culture media. Exogenous TGF-beta1 induced protection and neutralizing TGF-beta1 antibody prevented the cytoprotection by volatile anesthetics against hydrogen peroxide-induced HK-2 cell necrosis.
  
  
  CONCLUSIONS
  Volatile anesthetics induce a cytoprotective signaling cascade in proximal tubule cells via membrane externalization of PS initiating TGF-beta1-mediated cytoprotection.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032-3784, USA. tl128@columbia.edu
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kim
authors.forename: Jeehee
authors.initials: J
authors.lastname: Kim
authors.forename: Nala
authors.initials: N
authors.lastname: Kim
authors.forename: Charles W
authors.initials: CW
authors.lastname: Emala
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology* / Q000627:therapeutic use; D000906:Antibodies / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000378:metabolism / Q000517:prevention & control; D010718:Phosphatidylserines / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D018685:Anesthetics, Inhalation; D000906:Antibodies; D010718:Phosphatidylserines; D016212:Transforming Growth Factor beta; D006861:Hydrogen Peroxide