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* The Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada;
Departments of Medicine,
Microbiology & Immunology, and
Pathology, University of Western Ontario, London, Ontario, Canada; and
¶ Lawson Health Research Institute, London, Ontario, Canada
Renal ischemia-reperfusion injury (IRI) can result in acute renal failure with mortality rates of 50% in severe cases. NK cells are important participants in early-stage innate immune responses. However, their role in renal tubular epithelial cell (TEC) injury in IRI is currently unknown. Our data indicate that NK cells can kill syngeneic TEC in vitro. Apoptotic death of TEC in vitro is associated with TEC expression of the NK cell ligand Rae-1, as well as NKG2D on NK cells. In vivo following IRI, there was increased expression of Rae-1 on TEC. FACS analyses of kidney cell preparations indicated a quantitative increase in NKG2D-bearing NK cells within the kidney following IRI. NK cell depletion in wild-type C57BL/6 mice was protective, while adoptive transfer of NK cells worsened injury in NK, T, and B cell-null Rag2–/–
c–/– mice with IRI. NK cell-mediated kidney injury was perforin (PFN)-dependent as PFN–/– NK cells had minimal capacity to kill TEC in vitro compared with NK cells from wild-type, FasL-deficient (gld), or IFN-–/– mice. Taken together, these results demonstrate for the first time that NK cells can directly kill TEC and that NK cells contribute substantially to kidney IRI. NK cell killing may represent an important underrecognized mechanism of kidney injury in diverse forms of inflammation, including transplantation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by the Canadian Institutes of Health Research (to A.M.J.), the Kidney Foundation of Canada (to Z.-X.Z. and A.M.J.), the Heart and Stroke Foundation of Canada (Z.-X.Z.), and the Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada. A.M.J. is also supported as the Wyeth-Canadian Institute for Health Research Chair in Transplantation.
2 Address correspondence and reprint requests to Dr. Zhu-Xu Zhang and Dr. Anthony M. Jevnikar, Department of Medicine, University of Western Ontario, University Hospital, A10-113, 339 Windermere Road, London, Ontario N6A 5A5, Canada. E-mail addresses: zhuxu.zhang{at}lhsc.on.ca and jevnikar{at}uwo.ca
3 Abbreviations used in this paper: IRI, ischemia-reperfusion injury; PFN, perforin; 7-AAD, 7-aminoactinomycin D; TEC, tubular epithelial cell.
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  Y. Wang, R. John, J. Chen, J. A. Richardson, J. M. Shelton, M. Bennett, X. J. Zhou, G. T. Nagami, Y. Zhang, Q. Q. Wu, et al. IRF-1 Promotes Inflammation Early after Ischemic Acute Kidney Injury J. Am. Soc. Nephrol., July 1, 2009; 20(7): 1544 - 1555. [Abstract] [Full Text] [PDF]
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