Akiko Takahata1, Satoko Arai2, Emiri Hiramoto2, Kento Kitada2,3, Rina Kato1, Yuko Makita1, Hitoshi Suzuki1, Junichiro Nakata1, Kimi Araki4, Toru Miyazaki5,6, Yusuke Suzuki7. 1. Department of Nephrology, Juntendo University, Tokyo, Japan. 2. Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo, Japan. 3. Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore. 4. Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan. 5. Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo, Japan yusuke@juntendo.ac.jp tm@m.u-tokyo.ac.jp. 6. Leading Advanced Projects for Medical Innovation, Japan Agency for Medical Research and Development, Tokyo, Japan. 7. Department of Nephrology, Juntendo University, Tokyo, Japan yusuke@juntendo.ac.jp tm@m.u-tokyo.ac.jp.
Abstract
BACKGROUND: IgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages' function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition. METHODS: We established an AIM-deficient IgAN model (AIM -/- gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model (IgA -/- gddY) was also generated to further determine the role of AIM. RESULTS: In both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although AIM -/- gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45+ leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in IgA -/- gddY mice. CONCLUSIONS: AIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation.
BACKGROUND:IgAnephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages' function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition. METHODS: We established an AIM-deficient IgAN model (AIM -/- gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model (IgA -/- gddY) was also generated to further determine the role of AIM. RESULTS: In both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although AIM -/- gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45+ leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in IgA -/- gddY mice. CONCLUSIONS: AIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation.
Authors: Hitoshi Suzuki; Krzysztof Kiryluk; Jan Novak; Zina Moldoveanu; Andrew B Herr; Matthew B Renfrow; Robert J Wyatt; Francesco Scolari; Jiri Mestecky; Ali G Gharavi; Bruce A Julian Journal: J Am Soc Nephrol Date: 2011-09-23 Impact factor: 10.121
Authors: Satoko Arai; John M Shelton; Mingyi Chen; Michelle N Bradley; Antonio Castrillo; Angie L Bookout; Puiying A Mak; Peter A Edwards; David J Mangelsdorf; Peter Tontonoz; Toru Miyazaki Journal: Cell Metab Date: 2005-03 Impact factor: 27.287
Authors: Angelique L Rops; Johan van der Vlag; Cor W Jacobs; Henry B Dijkman; Joost F Lensen; Tessa J Wijnhoven; Lambert P van den Heuvel; Toin H van Kuppevelt; Jo H Berden Journal: Kidney Int Date: 2004-12 Impact factor: 10.612
Authors: Z Moldoveanu; R J Wyatt; J Y Lee; M Tomana; B A Julian; J Mestecky; W-Q Huang; S R Anreddy; S Hall; M C Hastings; K K Lau; W J Cook; J Novak Journal: Kidney Int Date: 2007-03-07 Impact factor: 10.612