title: Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury.
abstract: Natural killer T (NKT) cells are the major early-acting immune cell type and fundamental immune modulators in ischemia-reperfusion injury (IRI). Because lymphocytes are exposed to various oxygen tensions under pathophysiologic conditions, we hypothesize that hypoxia-inducible factors (HIFs) have roles in NKT cell activation, and thus determine the final outcome of renal IRI. In this study, we used Lck-Cre transgenic mice to specifically disrupt HIF-2α in T/NKT cells and found that HIF-2α knockout led to upregulated Fas ligand expression on peripheral NKT cells, but not on conventional T cells. HIF-2α knockout promoted infiltration of NKT cells into ischemic kidneys and exacerbated IRI, which could be mitigated by in vivo NK1.1(+) cell depletion or Fas ligand blockade. Compared with wild-type NKT cells, HIF-2α(-/-) NKT cells adoptively transferred to Rag1-knockout mice elicited more severe renal injury, and these mice were not protected by CGS21680, an adenosine A2A receptor agonist. Mechanistically, hypoxia-induced expression of adenosine A2A receptor in NKT cells and CGS21680-induced cAMP production in thymocytes were HIF-2α-dependent. Hydrogen peroxide-induced Fas ligand expression on thymic wild-type NKT cells was significantly attenuated by CGS21680 treatment, but this effect was lost in HIF-2α(-/-) NKT cells. Finally, CGS21680 and LPS, an inducer of HIF-2α in endothelium, synergistically reduced renal IRI substantially, but this effect was absent in Mx1-Cre-induced global HIF-2α-knockout mice. Taken together, our results reveal a hypoxia/HIF-2α/adenosine A2A receptor axis that restricts NKT cell activation when confronted with oxidative stress and thus protects against renal IRI.
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Urology, The Affiliated School of Clinical Medicine of Xuzhou Medical College, Xuzhou Central Hospital, Xuzhou, China;
authors.forename: Conghui
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;
authors.forename: Huijuan
authors.initials: H
authors.lastname: Dai
authors.affiliation: Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China; and.
authors.forename: Jianquan
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Urology, The Affiliated School of Clinical Medicine of Xuzhou Medical College, Xuzhou Central Hospital, Xuzhou, China;
authors.forename: Yang
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Cui
authors.affiliation: The Central Laboratory of Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Longmei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; zhangming1973@yeah.net xiaqiang@shsmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; zhangming1973@yeah.net xiaqiang@shsmu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D007668:Kidney / Q000098:blood supply*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D055611:Natural Killer T-Cells / Q000502:physiology*; D043705:Receptor, Adenosine A2A; D015427:Reperfusion Injury / Q000276:immunology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D043705:Receptor, Adenosine A2A; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: hypoxia; immunology; ischemia-reperfusion; ischemic renal failure