The role of heme oxygenase 1 in rapamycin-induced renal dysfunction after ischemia and reperfusion injury.
Ischemia and reperfusion injury (IRI) is the main etiology of acute renal failure in native and transplanted kidneys. In the transplantation field, immunosuppressive drugs may play an additional role in acute graft dysfunction. Rapamycin may impair renal regeneration post IRI. Heme oxygenase 1 (HO-1) is a protective gene with anti-inflammatory and anti-apoptotic actions. We investigated whether HO-1 played a role in rapamycin-induced renal dysfunction in an established model of IRI. Rapamycin (3 mg/kg) was administered to mice before being subjected to 45 min of ischemia. Animals subjected to IRI presented with impaired renal function that peaked at 24 h (2.05+/-0.23 mg/dl), decreasing thereafter. Treatment with rapamycin caused even more renal dysfunctions (2.30+/-0.33 mg/dl), sustained up to 120 h after reperfusion (1.54+/-0.4 mg/dl), when compared to the control (0.63+/-0.09 mg/dl, P<0.05). Rapamycin delayed tubular regeneration that was normally higher in the control group at day 5 (68.53+/-2.30 vs 43.63+/-3.11%, P<0.05). HO-1 was markedly upregulated after IRI and its expression was even enhanced by rapamycin (1.32-fold). However, prior induction of HO-1 by cobalt protoporphyrin improved the renal dysfunction imposed by rapamycin, mostly at later time points. These results demonstrated that rapamycin used in ischemic-injured organs could also negatively affect post-transplantation recovery. Modulation of HO-1 expression may represent a feasible approach to limit rapamycin acute toxicity.
Gonçalves
G M
GM
Laboratório de Imunologia Clínica e Experimental, Division of Nephrology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil.
Cenedeze
M A
MA
Feitoza
C Q
CQ
Wang
P M H
PM
Bertocchi
A P F
AP
Damião
M J
MJ
Pinheiro
H S
HS
Antunes Teixeira
V P
VP
dos Reis
M A
MA
Pacheco-Silva
A
A
Câmara
N O S
NO
D058186:Acute Kidney Injury / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000150:complications / Q000201:enzymology / Q000503:physiopathology*; D020123:Sirolimus / Q000009:adverse effects* / Q000494:pharmacology
D007166:Immunosuppressive Agents; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D020123:Sirolimus