title: Reduction in Renal Ischemia-Reperfusion Injury in Mice by a Phosphoinositide 3-Kinase p110gamma-Specific Inhibitor.
abstract: BACKGROUND
  Although renal ischemia-reperfusion injury (IRI) can cause delayed graft function, a targeted therapy is not yet available. Because phosphoinositide 3-kinases (PI3K) p110γ and p110δ play important roles in immune cell migration and function, we investigated the effects of PI3K p110γ- and p110δ-specific inhibitors in a murine renal IRI model.
  
  
  METHODS
  Renal function was assessed by serum creatine and hematoxylin-eosin staining. Immune cell migration was assessed by flow cytometry and an in vitro cell migration assay using Transwell plates. Gene expression analysis and a multiplex cytokine/chemokine assay were performed to find cytokines/chemokines whose expression was upregulated in renal IRI and affected by p110γ-specific inhibitor.
  
  
  RESULTS
  The PI3K p110γ-specific inhibitor, but not p110δ-specific inhibitor, significantly reduced serum creatine levels and acute tubular necrosis. These were accompanied by reduced infiltration of B cells and reduced expression of CXCL9, a CXCR3 ligand, suggesting that p110γ plays an important role in B-cell migration toward injured kidneys. An in vitro cell migration assay revealed for the first time that B-cell migration to injured kidney cells and to CXCL9 requires p110γ.
  
  
  CONCLUSIONS
  p110γ-specific inhibitor ameliorates renal IRI by reducing necrosis and immune cell migration. This inhibitor may have the potential to reduce renal graft failure caused by renal IRI.
authors.affiliation: 1 Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 2 Department of Medicine Graduate School, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 3 Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul, South Korea. 4 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 5 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.forename: Dong-Cheol
authors.initials: DC
authors.lastname: Woo
authors.forename: Seo Jeong
authors.initials: SJ
authors.lastname: Joo
authors.forename: Youyol
authors.initials: Y
authors.lastname: Song
authors.forename: Jae Jin
authors.initials: JJ
authors.lastname: Lee
authors.forename: Chul-Woong
authors.initials: CW
authors.lastname: Woo
authors.forename: Sang Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Seokmann
authors.initials: S
authors.lastname: Hong
authors.forename: Yong Mee
authors.initials: YM
authors.lastname: Cho
authors.forename: Duck-Jong
authors.initials: DJ
authors.lastname: Han
mesh_terms: D000818:Animals; D002465:Cell Movement; D054370:Chemokine CXCL9 / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D003401:Creatine / Q000097:blood; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006085:Graft Survival; D007668:Kidney / Q000473:pathology*; D007683:Kidney Tubular Necrosis, Acute / Q000097:blood / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015427:Reperfusion Injury / Q000473:pathology*
chemical_list: D054370:Chemokine CXCL9; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D003401:Creatine; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; C485969:Cxcl9 protein, mouse; C421683:Pik3cd protein, mouse; C546764:Pik3cg protein, mouse