Reduction of ischemia-reperfusion injury in the rat kidney by FTY720, a synthetic derivative of sphingosine.
BACKGROUND
The current shortage of organ donors has led many centers to use marginal and nonheart-beating donors (NHBDs). Recent research has implicated the infiltration of lymphocytes as an important mediator of ischemia-reperfusion injury (IRI). FTY720 is an immunosuppressant that promotes lymphocyte sequestration into lymph nodes. The purpose of this study was to examine the potential for FTY720 to abrogate IRI when subjected to increasing ischemic times.


METHODS
Male Sprague-Dawley rats underwent bilateral flank incision with removal of the right kidney and clamping of the left hilum. Groups were divided into ischemia times of 45, 55, and 65min; each group was further divided into a control group (IRI only), IRI+FTY720 (1 mg/kg/d), and IRI+cyclosporine (15 mg/kg/d), n=4 per group.


RESULTS
Thre days after 45 min of ischemia, serum creatinine in the ischemia only (477+/-37 micromol/L) and cyclosporine groups (698+/-32 micromol/L) was significantly increased compared with the FTY720-treated animals (194+/-66 micromol/L). The beneficial effect of FTY720 was also observed at 55 and 65 min; indeed, FTY720-treated animals demonstrated signs of recovery from 65 min of ischemia whereas control and cyclosporine-treated animals required sacrifice between days 3 and 5. Treatment with FTY720 reduced renal damage assessed histologically and also reduced apoptosis and increased cell proliferation.


CONCLUSIONS
Treatment with FTY720 reduced IRI and prevented unrecoverable acute renal failure after significant ischemic injury. This study suggests that FTY720 may help improve the quality of grafts from NHBD and marginal donors by abrogating the IRI insult.
Delbridge
Michael S
MS
Department of Vascular Surgery, Northern General Hospital, Sheffield, UK.
Shrestha
Badri M
BM
Raftery
Andrew T
AT
El Nahas
A Meguid
AM
Haylor
John L
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D005500:Follow-Up Studies; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply*; D016030:Kidney Transplantation; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011409:Propylene Glycols / Q000138:chemical synthesis / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D018809:Proliferating Cell Nuclear Antigen; D011409:Propylene Glycols; D003404:Creatinine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine