Submitted on November 28, 2007
Accepted on May 12, 2008
Indoleamine 2,3-dioxygenase (IDO) activity promotes renal ischemia reperfusion injury
Kanishka Mohib1, Shuang Wang2, Qiunong Guan3, Andrew L Mellor4, Hongtao Sun5, Caigan Du6, and Anthony Micheal Jevnikar7*
1 Department of Microbiology and Immunology, University of Western Ontario, London, Canada
2 Robarts Research Institute, London, Canada
3 Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
4 Department of Medicine, Medical College of Georgia, Augusta, Georgia, United States
5 Lawson Health Research Institute, London, Canada; London Health Sciences Center, The Multi Organ transplant Program, London, Canada
6 Department of Urologic Sciences, University of British Columbia, Vancouver British Columbia, Canada
7 Medicine, University of Western Ontario, United States; Microbiology and Immunology, University of Western Ontario, London, Canada; Robarts Research Institute, University of Western Ontario, London, Canada; The Lawson Health Research Institute, London, Canada; The Multi-Organ Transplant Program, London Health Sciences Center, London, Canada
* To whom correspondence should be addressed. E-mail: jevnikar{at}uwo.ca.
Indoleamine 2,3-dioxygenase (IDO) catabolizes tryptophan to N-formyl kunurenine and has a pro-apoptotic role in renal tubular epithelial cells (TEC) in response to IFN-
and TNF-
in-vitro. TEC produce abundant amounts of IDO in-vitro in response to inflammation but the pathological role of 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 minutes at 32°C. Here we demonstrate up-regulation of IDO in renal tissue at 2 hrs after reperfusion which reached maximal levels at 24 hrs. Inhibition of IDO following IRI prevented the increase in serum creatinine observed in vehicle treated mice (86.4±25 mmol/L, n=11) when compared to mice treated with 1-methyl-d-tryptophan (1-MT), a specific inhibitor of IDO, (33.7±8.7mmol/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±2.0mmol/L, n= 6) following IRI as compared to wild type (WT) mice (123±30mmol/L, n= 9, p= 0.008). Our data suggest that attenuation of IDO may represent a novel strategy to reduce renal pathology as a result of ischemia/reperfusion.
