Kidney injury molecule–1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells
Takaharu Ichimura, Edwin J.P.v. Asseldonk, Benjamin D. Humphreys, Lakshman Gunaratnam, Jeremy S. Duffield, Joseph V. Bonventre
Takaharu Ichimura, Edwin J.P.v. Asseldonk, Benjamin D. Humphreys, Lakshman Gunaratnam, Jeremy S. Duffield, Joseph V. Bonventre
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Research Article Nephrology

Kidney injury molecule–1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells

Abstract

Following injury, the clearance of apoptotic and necrotic cells is necessary for mitigation and resolution of inflammation and tissue repair. In addition to macrophages, which are traditionally assigned to this task, neighboring epithelial cells in the affected tissue are postulated to contribute to this process. Kidney injury molecule–1 (KIM-1 or TIM-1) is an immunoglobulin superfamily cell-surface protein not expressed by cells of the myeloid lineage but highly upregulated on the surface of injured kidney epithelial cells. Here we demonstrate that injured kidney epithelial cells assumed attributes of endogenous phagocytes. Confocal images confirm internalization of apoptotic bodies within KIM-1–expressing epithelial cells after injury in rat kidney tubules in vivo. KIM-1 was directly responsible for phagocytosis in cultured primary rat tubule epithelial cells and also porcine and canine epithelial cell lines. KIM-1 was able to specifically recognize apoptotic cell surface-specific epitopes phosphatidylserine, and oxidized lipoproteins, expressed by apoptotic tubular epithelial cells. Thus, KIM-1 is the first nonmyeloid phosphatidylserine receptor identified to our knowledge that transforms epithelial cells into semiprofessional phagocytes.

Authors

Takaharu Ichimura, Edwin J.P.v. Asseldonk, Benjamin D. Humphreys, Lakshman Gunaratnam, Jeremy S. Duffield, Joseph V. Bonventre

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Figure 1

Kim-1–expressing tubule epithelial cells bind and internalize apoptotic bodies and necrotic debris in rat kidneys following ischemic injury.

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Kim-1–expressing tubule epithelial cells bind and internalize apoptotic ...
(A) By light microscopy, necrotic cellular debris (seen by differential interference contrast [DIC]) binds to apically located Kim-1 (dark brown) of surviving tubule epithelial cells (large arrows). An apoptotic body is seen in 1 Kim-1–positive epithelial cell (small arrow). (B) By fluorescence microscopy many DAPI-positive (blue) apoptotic bodies (large arrows) can be seen binding to the surface of Kim-1–positive (red) epithelial cells, and Kim-1–expressing cells have processes (red, small arrow) internalizing an apoptotic body (blue). In addition, apoptotic bodies have been internalized by Kim-1–positive epithelial cells (blue, arrowhead). (C) Confocal image of apoptotic cells (blue) localized in phagocytic cups (small arrows) on the Kim-1–positive (red) apical surface of tubular cells. An internalized apoptotic cell is indicated by a large arrow. L denotes the tubule lumen. (D) The proportion of Kim-1–positive tubules containing internalized apoptotic bodies was greater than adjacent Kim-1–negative tubules in the postischemic kidney. Neither Kim-1 nor apoptotic bodies were identified in the normal kidneys. *P = 0.01 (error bars indicate SD). (E) Kim-1–positive epithelial cells (red) binding many TUNEL-positive apoptotic bodies (green, large arrows) and internalizing other small apoptotic bodies (green, small arrow). (F) Kim-1–positive epithelial cells (red, large arrows) are surrounded by CD68-positive macrophages (green, small arrows), which do not express Kim-1 and are found only in the interstitium. Scale bar: 10 μm.