title: Osteopontin Blockade Attenuates Renal Injury After Ischemia Reperfusion by Inhibiting NK Cell Infiltration.
abstract: Renal ischemia-reperfusion (RIR) injury is a common occurrence after major surgery and shock, leading to acute kidney injury (AKI). Osteopontin (OPN) is a secreted glycoprotein that acts as a proinflammatory cytokine and activator of T lymphocytes. We hypothesized that blockade of OPN reduces the severity of inflammation and injury in RIR. Renal ischemia was induced in adult C57BL/6 mice via bilateral clamping of renal pedicles for 35 min, followed by reperfusion for 24 h. Anti-OPN antibody (Ab), nonimmunized isotype immunoglobulin G, or normal saline was injected intravenously at the time of reperfusion. Blood and kidneys were collected for analysis. At 24 h after RIR, OPN mRNA and protein levels were significantly increased in renal tissue compared with sham mice. In serum, elevated levels of blood urea nitrogen and creatinine were reduced in anti-OPN Ab-treated mice compared with vehicle. Anti-OPN Ab-treated mice also had decreased mRNA levels of injury markers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 compared with the vehicle. The histologic architecture and apoptosis of renal tissue were improved in the anti-OPN Ab-treated mice. In renal tissue, inflammatory cytokines interleukin 6 and tumor necrosis factor-α protein levels were reduced in the Ab-treated mice. Natural killer (NK) cell infiltration was decreased after anti-OPN Ab treatment, as was neutrophil infiltration, shown by reduced chemokine expression and Gr1 renal immunohistochemical staining. These findings demonstrate a beneficial role of OPN blockade in RIR associated with NK cell-mediated downregulation of inflammatory cytokines and chemokines. Administration of anti-OPN Ab may therefore serve as an immunomodulatory adjunct in the treatment of RIR-induced AKI.
authors: *Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, New York†Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York.
authors: Cindy
authors: C
authors: Cen
authors: Monowar
authors: M
authors: Aziz
authors: Weng-Lang
authors: WL
authors: Yang
authors: Jeffrey M
authors: JM
authors: Nicastro
authors: Gene F
authors: GF
authors: Coppa
authors: Ping
authors: P
authors: Wang
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007694:Killer Cells, Natural / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D053495:Osteopontin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury
chemical_list: D000906:Antibodies; D053495:Osteopontin