Sevoflurane protects against renal ischemia and reperfusion injury in mice via the transforming growth factor-beta1 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)-beta1. In this study, we tested the hypothesis that volatile anesthetic-mediated renal protection requires TGF-beta1 and SMAD3 signaling in vivo. We subjected TGF-beta1+/+, TGF-beta1+/-, SMAD3+/+, or SMAD3-/- mice to renal IR under anesthesia with pentobarbital sodium or with sevoflurane. Although TGF-beta1+/+ and SMAD3+/+ mice were significantly protected against renal IR injury under sevoflurane anesthesia with reduced necrosis and inflammation, TGF-beta1+/- mice and SMAD3-/- mice were not protected against renal IR with sevoflurane. Furthermore, a neutralizing TGF-beta1 antibody blocked renal protection with sevoflurane in TGF-beta1+/+ mice. Sevoflurane caused nuclear translocation of SMAD3 and reduced the TNF-alpha-induced nuclear translocation of NF-kappaB in primary cultures of proximal tubules from TGF-beta1+/+ but not in TGF-beta1+/- mice. Finally, sevoflurane protected against necrosis induced with hydrogen peroxide in primary cultures of proximal tubules from TGF-beta1+/+ mice or SMAD3+/+ mice but not in proximal tubules from TGF-beta1+/- or SMAD3-/- mice. Therefore, we demonstrate in this study that sevoflurane-mediated renal protection in vivo requires the TGF-beta1-->SMAD3 signaling pathway.
Lee
H Thomas
HT
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032-3784, USA. tl128@columbia.edu
Chen
Sean W C
SW
Doetschman
Thomas C
TC
Deng
Chuxia
C
D'Agati
Vivette D
VD
Kim
Mihwa
M
D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D007674:Kidney Diseases / Q000517:prevention & control*; D007679:Kidney Medulla / Q000187:drug effects / Q000473:pathology; D008738:Methyl Ethers / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D000077149:Sevoflurane; D051900:Smad3 Protein / Q000172:deficiency; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000502:physiology*
D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D016328:NF-kappa B; D012333:RNA, Messenger; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D000077149:Sevoflurane