Anti-inflammatory and antinecrotic effects of the volatile anesthetic sevoflurane in kidney proximal tubule cells.
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.
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032-3784, USA. tl128@columbia.edu
H Thomas
HT
Lee
Mihwa
M
Kim
Michael
M
Jan
Charles W
CW
Emala
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004847:Epithelial Cells / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007673:Kidney Cortex Necrosis / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000187:drug effects* / Q000503:physiopathology; D008738:Methyl Ethers / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology; D000099190:MAP-Kinase-Activated Kinase 2
D018685:Anesthetics, Inhalation; D048049:Extracellular Signal-Regulated MAP Kinases; D018840:HSP70 Heat-Shock Proteins; D006861:Hydrogen Peroxide; D018799:Intercellular Adhesion Molecule-1; D047908:Intracellular Signaling Peptides and Proteins; D008738:Methyl Ethers; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D000077149:Sevoflurane; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2