title: The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells.
abstract: Extracellular adenosine triphosphate (ATP) binds to purinergic receptors and, as a danger molecule, promotes inflammatory responses. Here we tested whether periodate-oxidized ATP (oATP), a P2X7 receptor (P2X7R) antagonist can attenuate renal ischemia-reperfusion injury and clarify the related cellular mechanisms. Treatment with oATP prior to ischemia-reperfusion injury decreased blood urea nitrogen, serum creatinine, the tubular injury score, and tubular epithelial cell apoptosis after injury. The infiltration of dendritic cells, neutrophils, macrophages, CD69+CD4+, and CD44+CD4+T cells was attenuated, but renal Foxp3+CD4+Treg infiltration was increased by oATP. The levels of IL-6 and CCL2 were reduced in the oATP group. Additionally, oATP treatment following injury improved renal function, decreased the infiltration of innate and adaptive effector cells, and increased the renal infiltration of Foxp3+CD4+Tregs. Post-ischemia-reperfusion injury oATP treatment increased tubular cell proliferation and reduced renal fibrosis. oATP treatment attenuated renal functional deterioration after ischemia-reperfusion injury in RAG-1 knockout mice; however, Treg depletion using PC61 abrogated the beneficial effects of oATP in wild-type mice. Furthermore, oATP treatment after transfer of Tregs from wild-type mice improved the beneficial effects of Tregs on ischemia-reperfusion injury, but treatment after transfer of Tregs from P2X7R knockout mice did not. Renal ischemia-reperfusion injury was also attenuated in P2X7R knockout mice. Experiments using bone marrow chimeras established that P2X7R expression on hematopoietic cells rather than non-hematopoietic cells, such as tubular epithelial cells, plays a major role in ischemia-reperfusion injury. Thus, oATP attenuated acute renal damage and facilitated renal recovery in ischemia-reperfusion injury by expansion of Tregs.
authors.affiliation: Transplantation Center, Seoul National University Hospital, Seoul, Korea; Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Tai Yeon
authors.initials: TY
authors.lastname: Koo
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jae-Ghi
authors.initials: JG
authors.lastname: Lee
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ji-Jing
authors.initials: JJ
authors.lastname: Yan
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Joon Young
authors.initials: JY
authors.lastname: Jang
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Kyung Don
authors.initials: KD
authors.lastname: Ju
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Miyeun
authors.initials: M
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Kook-Hwan
authors.initials: KH
authors.lastname: Oh
authors.affiliation: Transplantation Center, Seoul National University Hospital, Seoul, Korea; Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Curie
authors.initials: C
authors.lastname: Ahn
authors.affiliation: Transplantation Center, Seoul National University Hospital, Seoul, Korea; Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. Electronic address: jcyjs@dreamwiz.com.
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Yang
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D016654:Genes, RAG-1; D007113:Immunity, Innate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C017199:2',3'-dialdehyde ATP; D000255:Adenosine Triphosphate
keywords: innate immunity; ischemia-reperfusion injury; periodate-oxidized adenosine triphosphate; purinergic receptor; regulatory T cells