TGF-beta1 release by volatile anesthetics mediates protection against renal proximal tubule cell necrosis.
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.
Lee
H Thomas
HT
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032-3784, USA. tl128@columbia.edu
Kim
Mihwa
M
Kim
Jeehee
J
Kim
Nala
N
Emala
Charles W
CW
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*
D018685:Anesthetics, Inhalation; D000906:Antibodies; D010718:Phosphatidylserines; D016212:Transforming Growth Factor beta; D006861:Hydrogen Peroxide