Heme oxygenase 1 and renal ischemia and reperfusion injury: the impact of immunosuppressive drug.
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. Acute cyclosporine nephrotoxicity (ATN) can result from vasoconstriction of the afferent arterioles, which may exacerbate deceased renal transplantation. HO-1 is a protective gene with anti-inflammatory and anti-apoptotic actions. We investigated whether HO-1 played a role in cyclosporine-induced renal dysfunction in an established model of IRI.


METHODS
Cyclosporine (100 mg/kg) was administered to mice before being subjected to 45 min of ischemia. Blood and kidney samples were collected at 24, 48 and 120 h after surgery. Acute tubular necrosis and tubular regeneration were quantified. HO-1 gene transcripts were amplified by real-time PCR.


RESULTS
Animals subjected to IRI presented with impaired renal function that peaked at 24 h (2.05 +/- 0.23 mg/dL), decreasing thereafter. Treatment with cyclosporine caused even more renal dysfunction at 48 h, sustained up to 120 h after reperfusion (1.53 +/- 0.6 mg/dL), when compared to the controls (0.63 +/- 0.09 mg/dL, p < 0,05). Cyclosporine delayed tubular regeneration that was normally higher in controls at day 5 (67.0% vs. 37.6%, p < 0.05). HO-1 was markedly up-regulated after IRI, and its expression was decreased by cyclosporine (2.06 folds). However, prior induction of HO-1 by cobalt protoporphyrin improved renal dysfunction.


CONCLUSIONS
These results demonstrated that cyclosporine used in ischemic injured organs might also negatively affect post-transplantation recovery.
Gonçalves
Giselle Martins
GM
Laboratório de Imunologia Clínica e Experimental, Division of Nephrology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil.
Cenedeze
Marcos Antônio
MA
Feitoza
Carla Quarim
CQ
de Paula
Carolina Batista
CB
Macusso
Georgia Daniela
GD
Pinheiro
Helady Sanders
HS
Teixeira
Vicente de Paula Antunes
Vde P
dos Reis
Marlene Antônia
MA
Pacheco-Silva
Alvaro
A
Câmara
Niels Olsen Saraiva
NO
D000818:Animals; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000235:genetics / Q000503:physiopathology*; D014508:Urea / Q000097:blood
D007166:Immunosuppressive Agents; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D016572:Cyclosporine; D014508:Urea; D003404:Creatinine; D051547:Heme Oxygenase-1