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Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice

Nature Medicine volume 22, pages 183–193 (2016)Cite this article

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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.

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Figure 1: Impaired recovery from IRI-induced AKI in the absence of AIM.
Figure 2: Impaired clearance of intraluminal debris and defective tissue repair in AIM− mice.
Figure 3: KIM-1 as a ligand of AIM.
Figure 4: AIM-accumulation enhances debris engulfment mediated by KIM-1.
Figure 5: Free AIM in serum and its excretion into urine after AKI.
Figure 6: rAIM facilitates recovery from AKI.

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Acknowledgements

We thank M. Nagase, M. Nangaku, T. Fujita, M. Ono, T. Gohda, Y. Sonoda, T. Aruga, K. Kimura, T. Yasuda, Y. Ito and S. Matsuo for helpful advice and discussion; T. Sugaya for mProx24 cells; D. Ikeda and S. Yamashita for Cd36−/− mice; K. Yamamura and N. Takeda for help with animal experiments; A. Nishijima, K. Aoyama and M. Shinohara for general technical assistance; and S. Tomita and Y. Inoue for administrative cooperation. This work was supported by a Core Research for Evolutional Medical Science and Technology grant funded by the Agency for Medical Research and Development (AMED-CREST) (T.M.), a research grant by Onsendo Co., Ltd. (T.M.) and an operating grant from the Canadian Institutes of Health Research (HDK244945) (L.G.).

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Author notes

  1. Kento Kitada & Mayumi Mori

    Present address: Present addresses: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA (K.K.); Laboratory for Experimental Fetomaternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg, Hamburg, Germany (M.M.).,

  2. Satoko Arai and Kento Kitada: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan

    Satoko Arai, Kento Kitada, Tomoko Yamazaki, Ryosuke Takai, Yoji Tsugawa, Ryoichi Sugisawa, Ayaka Matsumoto, Mayumi Mori, Yasunori Yoshihara, Natsumi Maehara, Shunsuke Kusunoki & Toru Miyazaki

  2. Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada

    Xizhong Zhang & Lakshman Gunaratnam

  3. Department of Emergency and Critical Care Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Kent Doi & Naoki Yahagi

  4. Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan

    Akiko Takahata & Yusuke Suzuki

  5. Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Eisei Noiri

  6. Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Akira Nishiyama

  7. Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada

    Lakshman Gunaratnam

  8. Division of Nephrology, Department of Medicine, McGill University Health Centre, McGill University, Quebec, Canada

    Tomoko Takano

  9. 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

    Toru Miyazaki

  10. Max Planck—The University of Tokyo Center for Integrative Inflammology, Tokyo, Japan

    Toru Miyazaki

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Contributions

S.A. and K.K. performed the majority of experiments—S.A. performed flow cytometry and the in vitro experiments, including the phagocytosis assays, and K.K. did animal experiments and histology. Y.T. and T.Y. contributed to analysis of AKI models; X.Z. and L.G. handled AKI induction in KIM-1–deficient mice; R.T. did histology; R.S., A.M. and Y.Y. contributed to biochemical experiments; T.M. constructed most plasmids; M.M. did kidney cell dissociation; N.M. did immunoblotting of human and mouse sera; S.K. contributed to animal experiments; K.D., A.T., E.N., Y.S. and N.Y. prepared and analyzed human samples; A.N., S.A., T.T. and T.M. designed experiments; and T.M. supervised the whole study and wrote the paper.

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Correspondence to Toru Miyazaki.

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Arai, S., Kitada, K., Yamazaki, T. et al. Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice. Nat Med 22, 183–193 (2016). https://doi.org/10.1038/nm.4012

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