Abstract

Am J Nephrol. 2010;31(4):353-62. Epub 2010 Mar 16.

Isoflurane protects human kidney proximal tubule cells against necrosis via sphingosine kinase and sphingosine-1-phosphate generation.

Authors: Kim M, Kim M, Park SW, Pitson SM, Lee HT.

Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032-3784, USA.

Background/Aims
We previously showed that the inhalational Anaesthetic isoflurane protects against renal ischemia reperfusion injury in part via sphingosine kinase (SK)-mediated synthesis of sphingosine-1-phosphate (S1P). In this study, we tested the hypothesis that isoflurane directly targets renal proximal tubule cells via SK activation, S1P synthesis and activation of S1P receptors to initiate cytoprotective signaling.

Methods And Results
Isoflurane-mediated phosphorylation of extracellular signal-regulated kinase (ERK) and Akt and induction of HSP70 in human kidney proximal tubule (HK-2) cells were inhibited by dimethylsphingosine (DMS), an SK inhibitor, and VPC23019, an S1P(1/3) receptor selective antagonist, in HK-2 cells. A selective S1P(1) receptor agonist, SEW2781, mimicked isoflurane-induced phosphorylation of ERK and Akt and induction of HSP70. Moreover, isoflurane-mediated protection against H(2)O(2)-induced necrosis of HK-2 cells was significantly attenuated by an S1P(1/3) receptor antagonist, VPC23019, and by SK inhibitors DMS or 4-[[4- (4-chlorophenyl)-2-thiazolyl]amino]phenol. Finally, overexpression of the SK1 enzyme in HK-2 cells protected against H(2)O(2)-induced necrosis.

Conclusions
Collectively, our study demonstrates that S1P released via isoflurane-mediated SK1 stimulation produces direct anti-necrotic effects probably via S1P(1) receptor-mediated cytoprotective signaling (ERK/Akt phosphorylation and HSP70 induction) in HK-2 cells. Our findings may help to unravel the cellular signaling pathways of volatile Anaesthetic-mediated renal protection and lead to new therapeutic applications of volatile anesthetics during the perioperative period. 2010 S. Karger AG, Basel.

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Shock. 2007 Apr;27(4):373-9

Isoflurane improves survival and protects against renal and hepatic injury in murine septic peritonitis.

Authors: Lee HT, Emala CW, Joo JD, Kim M.

Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York 10032-3784, USA. tl128@columbia.edu

We have demonstrated that volatile anesthetics reduce inflammation after renal ischemia/reperfusion injury in vivo.

As hyperactive uncontrolled inflammation can lead to mortality and morbidity during early sepsis, we questioned whether the volatile Anaesthetic isoflurane could reduce mortality and protect against sepsis induced renal and hepatic dysfunction.

Mice were anesthetized with isoflurane or with pentobarbital and subjected to cecal ligation and puncture (CLP) to induce septic peritonitis.

Mice were anesthetized for an additional 3 h after CLP with either isoflurane or pentobarbital. Renal and hepatic function was assessed 24 h later and survival after CLP was assessed for 7 days.

To determine if isoflurane protects by reducing inflammation, we quantified renal tubular expression of pro-inflammatory (intercellular adhesion molecule 1, tumor necrosis factor alpha [TNF-alpha], and interleukin [IL] 1beta) messenger RNA with reverse transcriptase-polymerase chain reaction.

We also measured the plasma levels of the pro-inflammatory cytokines TNF-alpha, keratinocyte-derived chemokine (KC), and IL-6 and an anti-inflammatory cytokine IL-10.

Renal cortical apoptosis was also assessed 24 h after CLP. Twenty-four hours after the septic insult, isoflurane-treated mice had significantly improved renal and hepatic function compared with mice anesthetized with pentobarbital.

Renal cortices of isoflurane-treated mice had significantly reduced expression of intercellular adhesion molecule 1, TNF-alpha, and IL-1beta messenger RNA and showed less apoptosis. Isoflurane-treated mice had lower plasma levels of TNF-alpha, KC, and IL-6. Isoflurane-anesthetized mice also had significantly prolonged and increased survival compared with pentobarbital-anesthetized mice.

Therefore, isoflurane anesthesia conferred significant protection against renal and hepatic dysfunction and death after septic peritonitis and attenuated renal inflammation and apoptosis compared with pentobarbital anesthesia.

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