Sevoflurane-mediated TGF-β1 signaling in renal proximal tubule cells

Abstract

Several volatile anesthetics, including sevoflurane, protect against renal ischemia-reperfusion injury in vivo by reducing necrosis and inflammation. Furthermore, in cultured renal tubule cells, sevoflurane directly induced the phosphorylation of the cytoprotective kinases (ERK and Akt), upregulated 70-kDa heat shock protein (HSP70), and attenuated nuclear translocation of the proinflammatory transcription factor NF-κB. It has been shown that sevoflurane increases the release of transforming growth factor-β1 (TGF-β1) in human proximal tubule (HK-2) cells via externalization of plasma membrane phosphatidylserine (PS), and this increase in TGF-β1 protected HK-2 cells against hydrogen peroxide-mediated necrosis. In this study, we aimed to determine whether the sevoflurane-mediated phosphorylation of ERK and Akt, induction of HSP70, and reduction in NF-κB activation are due to TGF-β1 receptor-mediated signaling after PS externalization in HK-2 cells. Exogenous TGF-β1 and a liposome mixture containing PS mimicked sevoflurane-mediated ERK and Akt phosphorylation and HSP70 induction in HK-2 cells. Sevoflurane and TGF-β1 caused the nuclear translocation of the SMAD3 transcription factor in HK-2 cells. Furthermore, a neutralizing TGF-β1 antibody or exogenous annexin V to bind PS prevented sevoflurane-induced ERK and Akt phosphorylation and HSP70 induction in HK-2 cells. Finally, a TGF-β1 antibody and annexin V attenuated the reduction in nuclear translocation of NF-κB by sevoflurane. Therefore, we demonstrate in this study that sevoflurane-mediated cytoprotective and anti-inflammatory effects in HK-2 cells are at least partially due to the externalization of PS and activation of TGF-β1 signaling pathways.