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 whether in vivo fluorinated anesthetic use stimulates renal SM hydrolysis, causing accumulation of ceramide, an important signaling molecule.


METHODS
Mice were anesthetized with isoflurane or desflurane (fluorinated 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) levels were also determined. Isoflurane's effects on ceramide levels in cultured human proximal tubule (HK-2) cells/isolated mouse proximal tubule segments (PTS), and on in vitro 14C-SM hydrolysis were also assessed.


RESULTS
Isoflurane and desflurane, but not pentobarbital, increased 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 B1) 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 (acidic) SMase to effect in vitro 14C-SM hydrolysis. Isoflurane raised renal cortical sphingosine (and not just ceramide) levels, implying ongoing ceramidase activity.


CONCLUSIONS
Fluorinated anesthetics can stimulate renal cortical/tubule ceramide expression, presumably by stimulating SMase-mediated SM hydrolysis. Since ceramide is a potential mediator of tubule apoptosis/necrosis, these findings have potential relevance for the development of intra/post-operative acute renal failure.
Lochhead
K M
KM
Department of Medicine, University of Washington, Seattle, USA.
Zager
R A
RA
D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D002518:Ceramides / Q000032:analysis; D000077335:Desflurane; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D007530:Isoflurane / Q000031:analogs & derivatives* / Q000633:toxicity*; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D010424:Pentobarbital / Q000633:toxicity; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013110:Sphingosine / Q000032:analysis
D018685:Anesthetics, Inhalation; D002518:Ceramides; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D000077335:Desflurane; D007530:Isoflurane; D013108:Sphingomyelin Phosphodiesterase; D010424:Pentobarbital; D013110:Sphingosine