Cytoprotective Actions of FTY720 Modulate Severe Preservation Reperfusion Injury in Rat Renal Transplants.
BACKGROUND
Fingolimod (FTY720) is a potent agonist of sphingosine 1 phosphate receptors and thereby interferes with lymphocyte trafficking. We previously showed that FTY720 protects from mild preservation reperfusion injury induced by 4 hr of cold ischemia. The purpose of this study was to explore the role of FTY720 in ischemic injury and regeneration using a clinically relevant rat renal transplant model with 24 hr of cold ischemia.


METHODS
Donor kidneys were cold stored in the University of Wisconsin solution for 24 hr before transplantation into bilaterally nephrectomized syngeneic recipients (n=6 per group), which received 0.5 mg/kg/d FTY720 or vehicle through oral gavage. Grafts were harvested 2 or 7 days posttransplantation. Renal tissue was examined histologically, stained for apoptosis, proliferation, inflammatory cell infiltrates, and studied for transforming growth factor-beta, and tumor necrosis factor-alpha expression. Rat proximal tubular cells were incubated with 0.1 to 30 micromol/L of phosphorylated FTY720 to test for in vitro cytopathic effects.


RESULTS
FTY720 induced peripheral lymphopenia and significantly reduced intragraft CD3 and ED1 infiltrates. Acute tubular damage scores and graft function were not influenced by FTY720. Tubular apoptosis was significantly reduced, whereas the number of proliferating cell nuclear antigen-positive tubular cells were markedly increased. FTY720 attenuated renal tumor necrosis factor-alpha and transforming growth factor-beta expression. In vitro, pharmacologic concentrations up to 1 micromol/L of phosphorylated FTY720 did not affect tubular cell viability.


CONCLUSIONS
FTY720 confers tubular epithelial protection in the presence of severe preservation reperfusion injury. Beneficial effects may in part be due to reduction in cell-mediated immune mechanisms. Furthermore, FTY720 could be helpful in patients with delayed graft function.
Fuller
T Florian
TF
Department of Urology, Charité Universitaetsmedizin Berlin, Berlin, Germany.
Hoff
Uwe
U
Kong
Linghua
L
Naether
Melanie
M
Wagner
Philine
P
Nieminen-Kelhä
Melina
M
Nolting
Jochen
J
Luft
Friedrich C
FC
Hegner
Björn
B
Dragun
Duska
D
D000241:Adenosine; D000493:Allopurinol; D000818:Animals; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D005978:Glutathione; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007249:Inflammation / Q000473:pathology; D007328:Insulin; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D019188:Organ Preservation Solutions; D011409:Propylene Glycols / Q000627:therapeutic use*; D011887:Raffinose; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D007328:Insulin; D019188:Organ Preservation Solutions; D011409:Propylene Glycols; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D000068876:Fingolimod Hydrochloride; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose; D013110:Sphingosine