Sevoflurane protects against renal ischemia and reperfusion injury in mice via the transforming growth factor-β1 pathway

We previously demonstrated that several clinically utilized volatile anesthetics including sevoflurane protected against renal ischemia-reperfusion (IR) injury by reducing necrosis and inflammation in vivo. We also demonstrated that volatile anesthetics produced direct anti- necrotic and anti- inflammatory effects in cultured renal tubules via mechanisms involving the externalization of phosphatidylserine and subsequent release of transforming growth factor (TGF)-beta(1). In this study, we tested the hypothesis that volatile anesthetic- mediated renal protection requires TGF-beta(1) and SMAD3 signaling in vivo. We subjected TGF-beta(1) +/+, TGF-beta(1) +/-, SMAD3+/+, or SMAD3-/- mice to renal IR under anesthesia with pentobarbital sodium or with sevoflurane. Although TGF-beta(1) +/+ and SMAD3 +/+ mice were significantly protected against renal IR injury under sevoflurane anesthesia with reduced necrosis and inflammation, TGF-beta(1) +/+ mice and SMAD3 +/+ mice were not protected against renal IR with sevoflurane. Furthermore, a neutralizing TGF-beta(1) antibody blocked renal protection with sevoflurane in TGF-beta(1) +/+ mice. Sevoflurane caused nuclear translocation of SMAD3 and reduced the TNF-alpha-induced nuclear translocation of NF-kappa B in primary cultures of proximal tubules from TGF-beta(1) +/+ but not in TGF-beta(1) +/- mice. Finally, sevoflurane protected against necrosis induced with hydrogen peroxide in primary cultures of proximal tubules from TGF-beta(1) +/+ mice or SMAD3 +/+ mice but not in proximal tubules from TGF-beta(1) +/- or SMAD3 -/- mice. Therefore, we demonstrate in this study that sevoflurane- mediated renal protection in vivo requires the TGF- beta(1) -> SMAD3 signaling pathway.