KIM-1–mediated phagocytosis reduces acute injury to the kidney
Li Yang, Craig R. Brooks, Sheng Xiao, Venkata Sabbisetti, Melissa Y. Yeung, Li-Li Hsiao, Takaharu Ichimura, Vijay Kuchroo, Joseph V. Bonventre
Li Yang, Craig R. Brooks, Sheng Xiao, Venkata Sabbisetti, Melissa Y. Yeung, Li-Li Hsiao, Takaharu Ichimura, Vijay Kuchroo, Joseph V. Bonventre
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Research Article Nephrology

KIM-1–mediated phagocytosis reduces acute injury to the kidney

Abstract

Kidney injury molecule 1 (KIM-1, also known as TIM-1) is markedly upregulated in the proximal tubule after injury and is maladaptive when chronically expressed. Here, we determined that early in the injury process, however, KIM-1 expression is antiinflammatory due to its mediation of phagocytic processes in tubule cells. Using various models of acute kidney injury (AKI) and mice expressing mutant forms of KIM-1, we demonstrated a mucin domain–dependent protective effect of epithelial KIM-1 expression that involves downregulation of innate immunity. Deletion of the mucin domain markedly impaired KIM-1–mediated phagocytic function, resulting in increased proinflammatory cytokine production, decreased antiinflammatory growth factor secretion by proximal epithelial cells, and a subsequent increase in tissue macrophages. Mice expressing KIM-1Δmucin had greater functional impairment, inflammatory responses, and mortality in response to ischemia- and cisplatin-induced AKI. Compared with primary renal proximal tubule cells isolated from KIM-1Δmucin mice, those from WT mice had reduced proinflammatory cytokine secretion and impaired macrophage activation. The antiinflammatory effect of KIM-1 expression was due to the interaction of KIM-1 with p85 and subsequent PI3K-dependent downmodulation of NF-κB. Hence, KIM-1–mediated epithelial cell phagocytosis of apoptotic cells protects the kidney after acute injury by downregulating innate immunity and inflammation.

Authors

Li Yang, Craig R. Brooks, Sheng Xiao, Venkata Sabbisetti, Melissa Y. Yeung, Li-Li Hsiao, Takaharu Ichimura, Vijay Kuchroo, Joseph V. Bonventre

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Figure 1

Decreased phagocytic function of KIM-1Δmucin in PTCs.

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Decreased phagocytic function of KIM-1Δmucin in PTCs. (A) Anti–KIM-1 imm...
(A) Anti–KIM-1 immunostaining (red) in primary PTCs from both WT KIM-1 and KIM-1Δmucin mice (left panel) and LLC-PK1 cells transfected with empty vector (control), KIM-1 or KIM-1Δmucin (right panel) exposed to apoptotic lymphocytes (green). Scale bar: 20 μm. (B) The percentage of PTCs that internalized apoptotic lymphocytes was reduced in the KIM-1Δmucin PTCs (n = 3). *P < 0.01; #P < 0.001. (C) Representative time course from 5 experiments of the uptake and acidification (red) of apoptotic cells (green) by KIM-1–expressing LLC-PK1 cells. Scale bar: 30 μm. (D) Representative images of cell outgrowth from coverslips in CHO cells expressing empty vector or KIM-1 (images are representative of 3 experiments). (E) TUNEL+ tubular cells in I/R kidneys from WT KIM-1 and KIM-1Δmucin mice (n = 5 mice/time point/group).*P < 0.01 vs. sham; #P < 0.01 vs. WT KIM-1. (F) Colocalization of KIM-1 and TUNEL+ cells (arrows in the left panel show KIM-1–binding apoptotic bodies). Scale bar: 50 μm. (G) Quantification of TUNEL+ cells in WT KIM-1 and KIM-1Δmucin mice 24 hours after I/R injury plus vehicle or I/R injury plus Baf (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001. (H) Representative images of apoptotic TUNEL+ cells in WT KIM-1 mice treated with Baf. Scale bar: 100 μm. (I) Quantification of KIM-1 mRNA expression in post–I/R injury KIM-1 and KIM-1Δmucin kidneys (n = 3). *P < 0.05; ***P < 0.001. (J) Quantification of luminal cellular debris in post–I/R injury WT KIM-1 and KIM-1Δmucin mice (n = 3). **P < 0.01. (K) Representative images of luminal debris (arrows) in KIM-1 and KIM-1Δmucin mice after I/R injury. Scale bar: 25 μm. Statistical comparisons were calculated by 2-tailed Student’s t test for the left 2 bars in B and by ANOVA followed by Bonferroni’s post-hoc analysis for all other panels. Δmucin, KIM-1Δmucin; WT, WT KIM-1.