title: Both PD-1 ligands protect the kidney from ischemia reperfusion injury.
abstract: Acute kidney injury (AKI) is a common problem in hospitalized patients that enhances morbidity and mortality and promotes the development of chronic and end-stage renal disease. Ischemia reperfusion injury (IRI) is one of the major causes of AKI and is characterized by uncontrolled renal inflammation and tubular epithelial cell death. Our recent studies demonstrated that regulatory T cells (Tregs) protect the kidney from ischemia reperfusion-induced inflammation and injury. Blockade of programmed death-1 (PD-1) on the surface of Tregs, prior to adoptive transfer, negates their ability to protect against ischemic kidney injury. The present study was designed to investigate the role of the known PD-1 ligands, PD-L1 and PD-L2, in kidney IRI. Administration of PD-L1 or PD-L2 blocking Abs prior to mild or moderate kidney IRI significantly exacerbated the loss of renal function, renal inflammation, and acute tubular necrosis compared with mice receiving isotype control Abs. Interestingly, blockade of both PD-1 ligands resulted in worse injury, dysfunction, and inflammation than did blocking either ligand alone. Genetic deficiency of either PD-1 ligand also exacerbated kidney dysfunction and acute tubular necrosis after subthreshold ischemia. Bone marrow chimeric studies revealed that PD-L1 expressed on non-bone marrow-derived cells is critical for this resistance to IRI. Finally, blockade of either PD-1 ligand negated the protective ability of adoptively transferred Tregs in IRI. These findings suggest that PD-L1 and PD-L2 are nonredundant aspects of the natural protective response to ischemic injury and may be novel therapeutic targets for AKI.
authors.affiliation: Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA 22908.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Jaworska
authors.affiliation: Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA 22908.
authors.forename: Joanna
authors.initials: J
authors.lastname: Ratajczak
authors.affiliation: Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA 22908.
authors.forename: Liping
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA 22908.
authors.forename: Kristen
authors.initials: K
authors.lastname: Whalen
authors.affiliation: Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA 22908.
authors.forename: Mana
authors.initials: M
authors.lastname: Yang
authors.affiliation: Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA 22908.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Stevens
authors.affiliation: Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA 22908 grk4n@virginia.edu.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Kinsey
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology* / Q000517:prevention & control; D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D015427:Reperfusion Injury / Q000276:immunology* / Q000517:prevention & control; D050378:T-Lymphocytes, Regulatory / Q000637:transplantation
chemical_list: D019138:Antibodies, Blocking; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C090509:Icam1 protein, mouse; D015850:Interleukin-6; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D018799:Intercellular Adhesion Molecule-1