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. 2008 Jul;295(1):F128-36.
doi: 10.1152/ajprenal.00577.2007. Epub 2008 Apr 23.

Sevoflurane protects against renal ischemia and reperfusion injury in mice via the transforming growth factor-beta1 pathway

H Thomas Lee  1 , Sean W C Chen, Thomas C Doetschman, Chuxia Deng, Vivette D D'Agati, Mihwa Kim
Affiliations

Sevoflurane protects against renal ischemia and reperfusion injury in mice via the transforming growth factor-beta1 pathway

H Thomas Lee et al. Am J Physiol Renal Physiol. 2008 Jul.

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)-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.

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Figures

Fig. 1.
Fig. 1.
A: representative gel images of semiquantitative RT-PCR results of transforming growth factor (TGF)-β1 and GAPDH mRNAs from TGF-β1+/+ and TGF-β1+/− mouse renal cortices. Representative images from 3 experiments are shown. B: densitometric quantifications of relative band intensities from RT-PCR reactions (n = 3). TGF-β1 mRNA band intensity was first normalized against GAPDH band intensity. *P < 0.001 vs. TGF-β1+/+ mice. Data presented as means ± SE.
Fig. 2.
Fig. 2.
Mouse plasma TGF-β1 concentration (in pg/ml) in TGF-β1+/+ mice (n = 10), TGF-β1+/− mice (n = 10), and TGF-β1+/+ mice injected with TGF-β1 neutralizing antibody (n = 4). Total plasma TGF-β1 concentrations were determined with ELISA. *P < 0.01 vs. TGF-β1+/+ mice. Data presented as means ± SE.
Fig. 3.
Fig. 3.
A: plasma creatinine (Cr in mg/dl) from studies with TGF-β1+/+ and +/− mice. Twenty-four hours after renal ischemia-reperfusion (IR), plasma Cr were measured in sham-operated mice (Sham; n = 4) or mice subjected to IR under pentobarbital sodium anesthesia (PB IR; n = 8 for TGF-β1+/+ mice, n = 9 for TGF-β1+/− mice) or sevoflurane anesthesia (Sevo IR; n = 6 for TGF-β1+/+ mice, n = 6 for TGF-β1+/− mice). Some TGF-β1+/+ mice were injected with TGF-β1 neutralizing antibody and subjected to renal IR under either pentobarbital sodium or sevoflurane anesthesia (n = 4). B: plasma Cr from studies with SMAD3+/+ and −/− mice. Twenty-four hours after renal IR, plasma Cr were measured in Sham (n = 4) or mice subjected to IR under PB IR (n = 5 for SMAD3+/+ and n = 6 for SMAD3−/− mice) or Sevo IR (n = 6 for SMAD3+/+ and n = 4 for SMAD3−/− mice). *P < 0.05 vs. sham-operated +/+ mice. #P < 0.05 vs. +/+ mice subjected to IR under pentobarbital sodium anesthesia. Data presented as means ± SE.
Fig. 4.
Fig. 4.
Representative of 6 photomicrographs (hematoxylin and eosin staining, magnification ×200) from studies with TGF-β1+/+ and +/− mice (A) or SMAD3+/+ and −/− mice (B). Pictures of outer medulla of the kidneys of sham-operated mice and mice subjected to renal IR injury under PB IR or Sevo IR anesthesia 24 h before. C: renal injury scores for the histologic appearance of acute tubular necrosis from sham-operated TGF-β1 mice (Sham) and mice subjected to renal IR during PB IR (n = 6 for TGF-β1+/+ mice, n = 6 for TGF-β1+/− mice) or during Sevo IR (n = 5 for TGF-β1+/+ mice, n = 6 for TGF-β1+/− mice). D: renal injury scores for the histologic appearance of acute tubular necrosis from sham-operated SMAD3 mice (Sham) and mice subjected to renal IR during PB IR (n = 4 for SMAD3+/+ and n = 4 for SMAD3−/− mice) or during Sevo IR (n = 6 for SMAD3+/+ and n = 4 for SMAD3−/− mice). *P < 0.05 vs. sham group. #P < 0.05 vs. +/+ PB IR group. Data are presented as means ± SE. Statistical analysis performed using the Kruskal-Wallis nonparametric test with Dunn posttest comparison.
Fig. 5.
Fig. 5.
A: representative image of EMSA studies for transcription factor NF-κB (top) and SMAD3 (bottom) binding activity in renal proximal tubules from TGF-β1+/+ and +/− mice. Percoll gradient-separated proximal tubules were maintained for 24 h and treated with vehicle (Veh), 10 ng/ml tumor necrosis factor-α (TNF-α), 2.2% sevoflurane (Sevo), or TNF-α plus 2.2% sevoflurane for 16 h. B: densitometric quantifications of relative band intensities from NF-κB (top) and SMAD3 (bottom) EMSA (n = 4). *P < 0.05 vs. vehicle-treated cells from TGF-β1+/+ mice. #P < 0.05 vs. TNF-α-treated cells from TGF-β1+/+ mice. Means ± SE.
Fig. 6.
Fig. 6.
LDH release after vehicle or H2O2 treatment (0–5 mM) for 4 h in proximal tubule cells cultured from TGF-β1+/+ and +/− mice (A) or SMAD3+/+ and −/− mice (B). Cells were treated with H2O2 16 h after treatment with carrier gas (room air plus 5% CO2) or with 2.2% sevoflurane in carrier gas (n = 6). *P < 0.05 vs. LDH released from +/+ mice proximal tubules with H2O2 injury after carrier gas pretreatment.
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