BACKGROUND/AIMS: 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. METHODS AND 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. Copyright 2007 S. Karger AG, Basel.
BACKGROUND/AIMS: 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. METHODS AND 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. Copyright 2007 S. Karger AG, Basel.
Authors: Leslie Gewin; Nada Bulus; Glenda Mernaugh; Gilbert Moeckel; Raymond C Harris; Harold L Moses; Ambra Pozzi; Roy Zent Journal: J Am Soc Nephrol Date: 2010-06-24 Impact factor: 10.121
Authors: Minjae Kim; Sang Won Park; Mihwa Kim; Sean W C Chen; William T Gerthoffer; Vivette D D'Agati; H Thomas Lee Journal: Am J Physiol Renal Physiol Date: 2010-05-19
Authors: H Thomas Lee; Sean W C Chen; Thomas C Doetschman; Chuxia Deng; Vivette D D'Agati; Mihwa Kim Journal: Am J Physiol Renal Physiol Date: 2008-04-23