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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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.).
The authors declare no competing financial interests.
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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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