Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction.
Acute kidney injury (AKI) frequently leads to systemic inflammation and extrarenal organ dysfunction. Volatile anesthetics are potent anti-inflammatory agents and protect against renal ischemia-reperfusion injury. Here, we sought to determine whether isoflurane, a commonly used volatile anesthetic, protects against AKI-induced liver and intestinal injury, the mechanisms involved in this protection, and whether this protection was independent of the degree of renal injury. Bilateral nephrectomy-induced AKI under pentobarbital sodium anesthesia led to severe hepatic and intestinal injury with periportal hepatocyte vacuolization, small intestinal necrosis, apoptosis, and proinflammatory mRNA upregulation. In contrast, isoflurane anesthesia reduced hepatic and intestinal injury after bilateral nephrectomy. Mechanistically, isoflurane anesthesia upregulated and induced small intestinal crypt sphingosine kinase-1 (SK1) as SK1 mRNA, protein, and enzyme activity increased with isoflurane treatment. Furthermore, isoflurane failed to protect mice treated with a selective SK inhibitor (SKI-II) or mice deficient in the SK1 enzyme against hepatic and intestinal dysfunction after bilateral nephrectomy, demonstrating the key role of SK1. Therefore, in addition to its potent anesthetic properties, isoflurane protects against AKI-induced liver and intestine injury via activation of small intestinal SK1 independently of the effects on the kidney. These findings may help to elucidate the cellular signaling pathways underlying volatile anesthetic-mediated hepatic and intestinal protection and result in novel clinical applications of volatile anesthetics to attenuate perioperative complications arising from AKI.
Department of Anesthesiology, College of Physicians and Surgeons, Anesthesiology Research Laboratories, Columbia University, P&S Box 46 PH-5 630 West 168th St., New York, NY 10032-3784, USA.
Minjae
M
Kim
Sang Won
SW
Park
Mihwa
M
Kim
Vivette D
VD
D'Agati
H Thomas
HT
Lee
D058186:Acute Kidney Injury; D000410:Alanine Transaminase / Q000097:blood; D018685:Anesthetics, Inhalation / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood; D004789:Enzyme Activation; D007421:Intestine, Small / Q000473:pathology; D007530:Isoflurane / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000517:prevention & control; D009392:Nephrectomy; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D000099157:Sphingosine Kinase
D000410:Alanine Transaminase; D018685:Anesthetics, Inhalation; D007530:Isoflurane; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase