Use of FTY 720 and ICAM-1 antisense oligonucleotides for attenuating chronic renal damage secondary to ischemia-reperfusion injury.
BACKGROUND
Chronic allograft nephropathy is the main cause of graft loss. Although many factors are involved in its development, ischemia-reperfusion injury has received increasing attention as a risk determinant. In a previous study of syngeneic renal transplantation and ischemia, we demonstrated a protective effect of acute damage by FTY 720 and antisense oligonucleotides of ICAM-1 (Oligos). The purpose of the current study was to evaluate the impact of these agents on the development of chronic graft damage in the same model.


METHODS
Lewis rat were used as donors and recipients. The harvested left kidney was kept in Collins solution for 2 hours. Recipient animals received treatment with FTY 720 or Oligos or saline. At 12 and 36 weeks after transplantation, creatinine clearance, GFR, proteinuria, and arterial blood pressure were recorded. Tissue from some animals were submitted for histological studies and quantification of mRNA TGF-beta1.


RESULTS
All groups showed decreased levels of GFR and creatinine clearence, but only the untreated animals showed significant deterioration compared to the pretransplant values (0.53 +/- 0.24 versus 0.21 +/- 0.24 at 36 weeks respectively; P < .05). Proteinuria was also significant in control animals at 36 weeks. Blood pressure showed a moderate increase in all groups. Histological analysis showed that treated animals had fewer signs of chronic damage according to the Banff score. All groups displayed slight increases in TGF-beta1 without differences among them.


CONCLUSIONS
In this model the use of FTY or antisense oligonucleotides of ICAM-1 were associated with less functional and morphological evidence of chronic graft damage secondary to an ischemia-reperfusion injury.
Troncoso
P
P
Unidad de Trasplante Renal, Pontificia Universidad Católica de Chile, Santiago, Chile. pabtron@med.puc.cl
Ortiz
A M
AM
Domínguez
J
J
Kahan
B D
BD
D000818:Animals; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007444:Inulin / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007677:Kidney Function Tests; D008297:Male; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011409:Propylene Glycols; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000150:complications / Q000517:prevention & control*; D013110:Sphingosine / Q000031:analogs & derivatives*
D016376:Oligonucleotides, Antisense; D011409:Propylene Glycols; D018799:Intercellular Adhesion Molecule-1; D007444:Inulin; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine