Indoleamine 2,3-dioxygenase expression promotes renal ischemia-reperfusion injury.
Indoleamine 2,3-dioxygenase (IDO) catabolizes tryptophan to N-formyl kynurenine and has a proapoptotic role in renal tubular epithelial cells (TEC) in response to IFN-gamma and TNF-alpha in vitro. TEC produce abundant amounts of IDO in vitro in response to inflammation but a pathological role for IDO in renal injury remains unknown. We investigated the role of IDO in a mouse model of renal ischemia-reperfusion injury (IRI). IRI was induced by clamping the renal pedicle of C57BL/6 mice for 45 min at 32 degrees C. Here, we demonstrate upregulation of IDO in renal tissue at 2 h after reperfusion which reached maximal levels at 24 h. Inhibition of IDO following IRI prevented the increase in serum creatinine observed in vehicle-treated mice (86.4 +/- 25 micromol/l, n = 11) compared with mice treated with 1-methyl-D-tryptophan, a specific inhibitor of IDO (33.7 +/- 8.7 micromol/l, n = 10, P = 0.031). The role of IDO in renal IRI was further supported by results in IDO-KO mice which maintained normal serum creatinine levels (32.5 +/- 2.0 micromol/l, n = 6) following IRI compared with wild-type mice (123 +/- 30 micromol/l, n = 9, P = 0.008). Our data suggest that attenuation of IDO expression within the kidney may represent a novel strategy to reduce renal injury as a result of ischemia reperfusion.
Mohib
Kanishka
K
Department of Medicine, University of Western Ontario, London, Ontario, Canada.
Wang
Shuang
S
Guan
Qiunong
Q
Mellor
Andrew L
AL
Sun
Hongtao
H
Du
Caigan
C
Jevnikar
Anthony M
AM
D000818:Animals; D004847:Epithelial Cells / Q000201:enzymology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology*; D007684:Kidney Tubules / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000209:etiology* / Q000473:pathology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C028129:tryptophan methyl ester; D014364:Tryptophan