FLUORINATED ANESTHETIC EXPOSURE ACTIVATES THE RENAL CORTICAL SPHINGOMYELINASE CASCADE

Background. Previous studies indicate that fluorinated anesthetics can enhance sphingomyelin (SM) hydrolysis in in vitro neuronal extracts. Renal cortex has substantial SM content. Hence, this study assessed wh ether in vivo fluorinated anesthetic use stimulates renal SM hydrolysi s, causing accumulation of ceramide, an important signaling molecule. Methods. Mice were anesthetized with isoflurane or desflurane (fluorin ated anesthetics). Pentobarbital anesthetized mice served as controls. After six hours, kidney cortex was assayed for ceramide. In selected experiments, renal cortical sphingosine and sphingomyelinase (SMase) l evels were also determined. Isoflurane's effects on ceramide levels in cultured human proximal tubule (HK-2) cells/isolated mouse proximal t ubule segments (PTS), and on in vitro C-14-SM hydrolysis were also ass essed. Results. Isoflurane and desflurane, but not pentobarbital, incr eased renal cortical ceramide levels (such as, 65% with isoflurane, P < 0.003). Isoflurane also raised PTS/HK-2 ceramide levels (by 25 to 35 %). Ceramidase inhibition (fumonisin B-1) did not block this ceramide accumulation in HK-2 cells. Isoflurane did not increase renal cortical /PTS SMase levels. However, it directly enhanced the ability of (acidi c) SMase to effect in vitro C-14-SM hydrolysis. Isoflurane raised rena l cortical sphingosine land not just ceramide) levels, implying ongoin g ceramidase activity. Conclusions. Fluorinated anesthetics can stimul ate renal cortical/tubule ceramide expression, presumably by stimulati ng SMase-mediated SM hydrolysis. Since ceramide is a potential mediato r of tubule apoptosis/necrosis, these findings have potential relevanc e for the development of intra/post-operative acute renal failure.