Several volatile anesthetics including sevoflurane protect against renal ischemia reperfusion (IR) injury in vivo by reducing necrosis and inflammation. Furthermore, in cultured renal tubule cells, sevoflurane directly induced the phosphorylation of the cytoprotective kinases, extracellular signal-regulated protein kinase (ERK) and Akt, upregulated heat shock protein 70 (HSP70) and attenuated nuclear translocation of the pro-inflammatory transcription factor NFB. Subsequently, we showed that sevoflurane increased the release of TGF-1 in human proximal tubule (HK-2) cells via externalization of plasma membrane phosphatidylserine (PS) and this increase in TGF-1 protected HK-2 cells against hydrogen peroxide-mediated necrosis. In this study, we wanted to determine whether the sevoflurane-mediated phosphorylation of ERK and Akt, induction of HSP70 and reduction in NFB activation are due to TGF-1 receptor mediated signaling after PS externalization in HK-2 cells. Exogenous TGF-1 as well as a liposome mixture containing PS mimicked sevoflurane-mediated ERK and Akt phosphorylation and HSP70 induction in HK-2 cells. Sevoflurane as well as TGF-1 caused the nuclear translocation of the SMAD3 transcription factor in HK-2 cells. Furthermore, a neutralizing TGF-1 antibody or exogenous annexin to bind PS prevented sevoflurane induced ERK and Akt phosphorylation and HSP70 induction in HK-2 cells. Finally, a TGF-1 antibody as well as annexin attenuated the reduction in nuclear translocation of NFB 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-1 signaling pathways.