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

H. Thomas Lee, Sean W.C. Chen, Thomas C. Doetschman, Chuxia Deng, Vivette D. D'Agati, Mihwa Kim

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

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)-β1. In this study, we tested the hypothesis that volatile anesthetic-mediated renal protection requires TGF-β1 and SMAD3 signaling in vivo. We subjected TGF-β1+/+, TGF- β1+/-, SMAD3+/+, or SMAD3-/- mice to renal IR under anesthesia with pentobarbital sodium or with sevoflurane. Although TGF-β1+/ + and SMAD3+/+ mice were significantly protected against renal IR injury under sevoflurane anesthesia with reduced necrosis and inflammation, TGF-β1+/- mice and SMAD3-/- mice were not protected against renal IR with sevoflurane. Furthermore, a neutralizing TGF-β1 antibody blocked renal protection with sevoflurane in TGF-β1+/+ mice. Sevoflurane caused nuclear translocation of SMAD3 and reduced the TNF-α-induced nuclear translocation of NF-κB in primary cultures of proximal tubules from TGF-β1+/+ but not in TGF- β1+/- mice. Finally, sevoflurane protected against necrosis induced with hydrogen peroxide in primary cultures of proximal tubules from TGF-β1+/+ mice or SMAD3+/+ mice but not in proximal tubules from TGF-β1+/- or SMAD3-/- mice. Therefore, we demonstrate in this study that sevoflurane-mediated renal protection in vivo requires the TGF-β1→SMAD3 signaling pathway.

Original languageEnglish (US)
Pages (from-to)F128-F136
JournalAmerican Journal of Physiology - Renal Physiology
Volume295
Issue number1
DOIs
StatePublished - Jul 1 2008

Keywords

  • Acute renal failure
  • Inflammation
  • Necrosis
  • SMAD3

ASJC Scopus subject areas

  • Physiology
  • Urology

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