Reduction in Renal Ischemia-Reperfusion Injury in Mice by a Phosphoinositide 3-Kinase p110gamma-Specific Inhibitor

• Published in: Transplantation Vol. 99; no. 10; p. 2070
• Main Authors: Kim, Nayoung, Woo, Dong-Cheol, Joo, Seo Jeong, Song, Youyol, Lee, Jae Jin, Woo, Chul-Woong, Kim, Sang Tae, Hong, Seokmann, Cho, Yong Mee, Han, Duck-Jong
• Format: Journal Article
• Language: English
• Published: United States 01.10.2015
• Subjects: Animals; Cell Movement; Chemokine CXCL9 - metabolism; Class Ib Phosphatidylinositol 3-Kinase - metabolism; Creatine - blood; Enzyme Inhibitors - chemistry; Female; Gene Expression Profiling; Gene Expression Regulation; Graft Survival; Kidney - pathology; Kidney Tubular Necrosis, Acute - blood; Kidney Tubular Necrosis, Acute - metabolism; Mice; Mice, Inbred C57BL; Necrosis; Phosphatidylinositol 3-Kinases - metabolism; Reperfusion Injury - pathology
• ISSN: 1534-6080
• DOI: 10.1097/TP.0000000000000742

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. 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. 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. 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.