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: Satoko Arai, Kento Kitada, Tomoko Yamazaki, Ryosuke Takai, Xizhong Zhang, Yoji Tsugawa, Ryoichi Sugisawa, Ayaka Matsumoto, Mayumi Mori, Yasunori Yoshihara, Kent Doi, Natsumi Maehara, Shunsuke Kusunoki, Akiko Takahata, Eisei Noiri, Yusuke Suzuki, Naoki Yahagi, Akira Nishiyama, Lakshman Gunaratnam, Tomoko Takano, Toru Miyazaki
• Journal: Nature medicine (Nat Med) Vol. 22 Issue 2 Pg. 183-93 (Feb 2016) ISSN: 1546-170X [Electronic] United States
• PMID: 26726878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• CD5L protein, human
• Cd5l protein, mouse
• Havcr1 protein, mouse
• Hepatitis A Virus Cellular Receptor 1
• Membrane Proteins
• Receptors, Immunologic
• Receptors, Scavenger

Topics

• Acute Kidney Injury (etiology, genetics, pathology)
• Aged
• Aged, 80 and over
• Animals
• Apoptosis Regulatory Proteins (genetics)
• Enzyme-Linked Immunosorbent Assay
• Female
• HEK293 Cells
• Hepatitis A Virus Cellular Receptor 1
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Kidney (metabolism, pathology)
• Kidney Tubules, Proximal (metabolism)
• Macrophages (metabolism)
• Male
• Membrane Proteins
• Mice
• Mice, Knockout
• Middle Aged
• Necrosis
• Phagocytosis (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Immunologic (genetics)
• Receptors, Scavenger (metabolism)
• Reperfusion Injury (complications, genetics, pathology)