Prevention of renal ischemic reperfusion injury using FTY 720 and ICAM-1 antisense oligonucleotides.
BACKGROUND
Renal damage secondary to ischemia-reperfusion injuries (I-R) is frequent in organ transplantation and adversely affects the graft survival. An important component of this damage is caused by initial adhesion of neutrophils and lymphocytes to endothelial cells. FTY 720, which induces lymphopenia, has previously been shown to display protective effects in models of I-R. The purpose of the present study was to evaluate the combination of FTY 720 and intracellular adhesion molecule and ICAM-1 antisense oligonucleotides (AS-oligos), an agent designed to block the adhesion process.


METHODS
Sprague-Dawley rats underwent syngenic kidney transplantation after donor kidneys had been preserved in cold solution for 2 hours. The treatment groups included: (1) FTY 720 (1 mg/kg) before reperfusion, (2) AS-oligos (2 mg/kg) during kidney perfusion, and (3) the combination of FTY 720 and AS-oligos. All animals were followed daily after transplantation; some were sacrificed on the second day for histologic analysis.


RESULTS
All treated groups showed a maximal serum creatinine that was significantly less than the control (group 1: 2.76 +/- 1.4, group 2: 2.44 +/- 2.05, group 3: 1.51 +/- 0.42, and control: 4.04 +/- 0.5; P <.01) and returned to the basal value earlier. Also, treated animals showed less histologic stigmata of acute tubular damage. FTY 720 and AS-oligos used in combination showed a mild additive effect.


CONCLUSIONS
The use of FTY 720 and/or AS-oligos significantly prevents functional renal damage secondary to I-R, displaying a mild additive effect in this model. Both agents offer the advantage of use during the donor and the graft operations.
Ortiz
A M
AM
Unidad de Trasplante Renal, Pontificia Universidad Catolica de Chile, Santiago, Chile.
Troncoso
P
P
Kahan
B D
BD
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology*; D015427:Reperfusion Injury / Q000517:prevention & control*; D013110:Sphingosine / Q000031:analogs & derivatives; D013873:Thionucleotides / Q000627:therapeutic use; D014185:Transplantation, Isogeneic
D007166:Immunosuppressive Agents; D016376:Oligonucleotides, Antisense; D011409:Propylene Glycols; D013873:Thionucleotides; D018799:Intercellular Adhesion Molecule-1; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine