Abstract
Renal ischemia-reperfusion (IR) injury is a major clinical problem without effective therapy. We recently reported that volatile anesthetics protect against renal IR injury, in part, via their anti-inflammatory properties. In this study, we demonstrate the anti-inflammatory and antinecrotic effects of sevoflurane in cultured kidney proximal tubule cells and probed the mechanisms of sevoflurane-induced renal cellular protection. To mimic inflammation, human kidney proximal tubule (HK-2) cells were treated with tumor necrosis factor-alpha (TNF-alpha; 25 ng/ml) in the presence or absence of sevoflurane. In addition, we studied the effects of sevoflurane pretreatment on hydrogen peroxide (H2O2)-induced necrotic cell death in HK-2 or porcine proximal tubule (LLC-PK1) cells. We demonstrate that sevoflurane suppressed proinflammatory effects of TNF-alpha evidenced by attenuated upregulation of proinflammatory cytokine mRNA (TNF-alpha, MCP-1) and ICAM-1 protein and reduced nuclear translocation of the proinflammatory transcription factors NF-kappaB and AP-1. Sevoflurane reduced necrotic cell death induced with H2O2 in HK-2 cells as well as in LLC-PK1 cells. Sevoflurane treatment resulted in phosphorylation of prosurvival kinases, ERK and Akt, and increased de novo HSP-70 protein synthesis without affecting the synthesis of HSP-27 or HSP-32. We conclude that sevoflurane has direct anti-inflammatory and antinecrotic effects in vitro in a renal cell type particularly sensitive to injury following IR injury. These mechanisms may, in part, account for volatile anesthetics' protective effects against renal IR injury.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anesthetics, Inhalation / pharmacology*
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Animals
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Cell Line
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Cell Survival / drug effects
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Cell Survival / physiology
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Epithelial Cells / chemistry
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Epithelial Cells / drug effects
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Epithelial Cells / physiology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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HSP70 Heat-Shock Proteins / metabolism
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Humans
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Hydrogen Peroxide / pharmacology
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Inflammation / physiopathology*
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Intercellular Adhesion Molecule-1 / analysis
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / physiology
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Intracellular Signaling Peptides and Proteins
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Kidney Cortex Necrosis / physiopathology*
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Kidney Tubules, Proximal / chemistry
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Kidney Tubules, Proximal / drug effects*
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Kidney Tubules, Proximal / physiopathology
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Methyl Ethers / pharmacology*
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NF-kappa B / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / analysis
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Sevoflurane
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Swine
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Transcription Factor AP-1 / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Necrosis Factor-alpha / physiology
Substances
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Anesthetics, Inhalation
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HSP70 Heat-Shock Proteins
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Intracellular Signaling Peptides and Proteins
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Methyl Ethers
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NF-kappa B
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RNA, Messenger
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Transcription Factor AP-1
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Tumor Necrosis Factor-alpha
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Intercellular Adhesion Molecule-1
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Sevoflurane
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Hydrogen Peroxide
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases