A role for HO-1 in renal function impairment in animals subjected to ischemic and reperfusion injury and treated with immunosuppressive drugs.
BACKGROUND
Ischemia/reperfusion injury (IRI) represents the single major antigen-independent factor implicated in pathogenesis of chronic graft dysfunction. Tacrolimus is a calcineurin inhibitor, which has been suggested to be helpful in cyclosporine-related chronic toxicity. Rapamycin has antiproliferative properties that may impair renal regeneration after IRI. Therefore, immunosuppressive drugs might impair renal graft outcome in those organs suffering IRI.


METHODS
C57B1/6 male mice subjected to 45 minutes of renal pedicle ligation were reperfused for 24 hours. Mice were treated with rapamycin, cyclosporine, or tacrolimus. Blood and renal tissue samples were collected at 24 hours after IRI. Urea levels were measured. Heme Oxygenase 1 (HO-1) gene transcript was amplified by a real-time polymerase chain reaction technique.


RESULTS
Animals treated with cyclosporine and subjected to IRI showed impaired renal function that peaked at 24 hours. Additional pretreatment with rapamycin produced even more impairment of renal function, when compared with controls. However, tacrolimus pretreatment was associated with a better renal outcome. HO-1 expression was upregulated after IRI by 2.6 arbitrary units at 24 hours. Rapamycin showed worse impairment of renal function.


CONCLUSIONS
Tacrolimus was not associated with worsening renal function when compared with animals just subjected to IRI. Upregulation of HO-1 may be an attractive approach to limit graft injury.
Feitoza
C Q
CQ
Laboratory of Experimental and Clinical Immunology, Nephrology Division, Federal University of São Paulo, São Paulo, Brazil.
Gonçalves
G M
GM
Bertocchi
A P F
AP
Wang
P W
PW
Damião
M J
MJ
Cenedeze
M A
MA
Teixeira
V P A
VP
Dos Reis
M A
MA
Pacheco-Silva
A
A
Câmara
N O S
NO
D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects; D051547:Heme Oxygenase-1 / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007674:Kidney Diseases / Q000201:enzymology / Q000276:immunology* / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000201:enzymology / Q000276:immunology* / Q000503:physiopathology; D020123:Sirolimus / Q000009:adverse effects; D016559:Tacrolimus / Q000009:adverse effects; D014158:Transcription, Genetic
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D051547:Heme Oxygenase-1; D020123:Sirolimus; D016559:Tacrolimus