title: Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice.
abstract: Acute kidney injury (AKI) is associated with prolonged hospitalization and high mortality, and it predisposes individuals to chronic kidney disease. To date, no effective AKI treatments have been established. Here we show that the apoptosis inhibitor of macrophage (AIM) protein on intraluminal debris interacts with kidney injury molecule (KIM)-1 and promotes recovery from AKI. During AKI, the concentration of AIM increases in the urine, and AIM accumulates on necrotic cell debris within the kidney proximal tubules. The AIM present in this cellular debris binds to KIM-1, which is expressed on injured tubular epithelial cells, and enhances the phagocytic removal of the debris by the epithelial cells, thus contributing to kidney tissue repair. When subjected to ischemia-reperfusion (IR)-induced AKI, AIM-deficient mice exhibited abrogated debris clearance and persistent renal inflammation, resulting in higher mortality than wild-type (WT) mice due to progressive renal dysfunction. Treatment of mice with IR-induced AKI using recombinant AIM resulted in the removal of the debris, thereby ameliorating renal pathology. We observed this effect in both AIM-deficient and WT mice, but not in KIM-1-deficient mice. Our findings provide a basis for the development of potentially novel therapies for AKI.
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Arai
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Kitada
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takai
authors.affiliation: Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Xizhong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Tsugawa
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Sugisawa
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mori
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Yoshihara
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kent
authors.initials: K
authors.lastname: Doi
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Maehara
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kusunoki
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Takahata
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Eisei
authors.identifier: http://orcid.org/0000-0002-9515-7582
authors.initials: E
authors.lastname: Noiri
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yahagi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada.|Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Lakshman
authors.initials: L
authors.lastname: Gunaratnam
authors.affiliation: Division of Nephrology, Department of Medicine, McGill University Health Centre, McGill University, Quebec, Canada.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.|Agency for Medical Research and Development-Core Research for Evolutional Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Tokyo, Japan.|Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazaki
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D057809:HEK293 Cells; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009336:Necrosis; D010587:Phagocytosis / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics*; D051116:Receptors, Scavenger / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C492821:CD5L protein, human; C117272:Cd5l protein, mouse; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger