Isoflurane Activates Intestinal Sphingosine Kinase to Protect against Renal Ischemia–Reperfusion-induced Liver and Intestine Injury

Abstract

Background Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury and often leads to multi-organ dysfunction and systemic inflammation. Volatile anesthetics have potent antiinflammatory effects and we aimed to determine whether the representative volatile anesthetic isoflurane protects against acute kidney injury-induced liver and intestinal injury and the mechanisms involved in this protection. Methods Mice were anesthetized with pentobarbital and subjected to 30 min of left renal ischemia after right nephrectomy followed by exposure to 4 h of equi-anesthetic doses of pentobarbital or isoflurane. Five hrs after renal IRI, plasma creatinine and alanine aminotransferase were measured. Liver and intestine tissues were analyzed for pro-inflammatory mRNAs, histology, sphingosine kinase-1 (SK1) immunoblotting, SK1 activity, and sphingosine-1-phosphate levels. Results Renal IRI with pentobarbital led to severe renal, hepatic, and intestinal injury with focused peri-portal hepatocyte vacuolization, small intestinal apoptosis and pro-inflammatory mRNA upregulation. Isoflurane protected against renal IRI and reduced hepatic and intestinal injury via induction of small intestinal crypt SK1 mRNA, protein and enzyme activity and increase in S1P. We confirmed the importance of SK1 as mice treated with a selective SK inhibitor (SKI-II) or mice deficient in SK1 enzyme were not protected against hepatic and intestinal dysfunction with isoflurane. Conclusions Taken together, we demonstrate that isoflurane protects against multi-organ injury after renal IRI via induction of the SK1/sphingosine-1-phosphate pathway. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated hepatic and intestinal protection and lead to new therapeutic applications of volatile anesthetics during the perioperative period.

Regulation of Mammalian Physiology, Development, and Disease by the Sphingosine 1-Phosphate and Lysophosphatidic Acid Receptors

“…Both LPA and S1P can also be found in ovarian cancer ascites at 5-to 10-fold the typical plasma concentration, although the specific cell types responsible for this production are unknown 30,31 . Synthesis of LPs by neutrophils, mast cells, mononuclear cells, intestinal, lung, and uterine epithelium, testis, ovaries, and kidneys has also been reported 32-39 . It is likely the production by these, and other as yet unidentified cell types, is responsible for managing the recruitment of specific cells to sites in the microenvironment within certain tissue structures, or to stimulate growth in isolated areas, such as the LPA-mediated neurogenesis of post-mitotic cortical neurons 40 .…”

miR-21 Contributes to Xenon-conferred Amelioration of Renal Ischemia–Reperfusion Injury in Mice

“…A growing body of evidence shows an organ protective effect against IRI in vivo by volatile anesthetics, such as isoflurane and xenon. 7–9,16 miRNAs are known to be involved in the development of IRI in several organs and in the protective effect of ischemic preconditioning. 25,26,29 Data obtained from cultured neuron-like cells suggest miR-203 might contribute to neuroprotection conferred by isoflurane preconditioning.…”

“…Preconditioning induced by volatile anesthetics, such as isoflurane confers significant protection against renal IRI. 7,8 The noble gas xenon (Xe) has many properties of an ideal anesthetic. 9–12 A series of investigations has shown that xenon exhibits organoprotective properties against IRI in the heart, brain, and kidney.…”

Isoflurane Post-conditioning Protects Against Intestinal Ischemia-Reperfusion Injury and Multiorgan Dysfunction via Transforming Growth Factor-β1 Generation

“…13 In situ labeling of fragmented DNA was performed with TUNEL stain (green fluorescence) using a commercially available in situ cell death detection kit (Roche, Indianapolis, IN) according to the instructions provided by the manufacturer. TUNEL-positive cells per high power field (hpf, 400X) were counted to quantify apoptosis.…”