Nayoung Kim1, Dong-Cheol Woo, Seo Jeong Joo, Youyol Song, Jae Jin Lee, Chul-Woong Woo, Sang Tae Kim, Seokmann Hong, Yong Mee Cho, Duck-Jong Han. 1. 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.
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.
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: Tiziana Palumbo; Kojiro Nakamura; Charles Lassman; Yoko Kidani; Steven J Bensinger; Ronald Busuttil; Jerzy Kupiec-Weglinski; Ali Zarrinpar Journal: Transplantation Date: 2017-02 Impact factor: 4.939
Authors: Christoph Wallner; Marius Drysch; Mustafa Becerikli; Sonja Verena Schmidt; Stephan Hahn; Johannes Maximilian Wagner; Felix Reinkemeier; Mehran Dadras; Alexander Sogorski; Maxi von Glinski; Marcus Lehnhardt; Björn Behr Journal: Sci Rep Date: 2021-06-15 Impact factor: 4.379