KIM-1–mediated phagocytosis reduces acute injury to the kidney
Li Yang, … , Vijay Kuchroo, Joseph V. Bonventre
Li Yang, … , Vijay Kuchroo, Joseph V. Bonventre
Published March 9, 2015
Citation Information: J Clin Invest. 2015;125(4):1620-1636. https://doi.org/10.1172/JCI75417.
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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 2

The KIM-1Δmucin mouse kidney is more susceptible to acute injury.

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The KIM-1Δmucin mouse kidney is more susceptible to acute injury. (A) Ch...
(A) Changes in SCr over time after I/R injury in WT KIM-1 and KIM-1Δmucin mice (n = 12/time point/group). *P < 0.001 and **P < 0.05 vs. sham; #P < 0.05 vs. KIM-1 WT. (B) Quantification of tubulointerstitial damage (n = 3/time point/group) and H&E-stained histological images of I/R kidneys. *P < 0.05. (C) Changes in SCr (n = 6/group) and mortality over time after cisplatin injection into KIM-1 and KIM-1Δmucin mice. *P < 0.001 and **P < 0.05 vs. control; #P < 0.05 vs. KIM-1 WT. (D and E) Cisplatin-induced acute toxic kidney injury. Quantification of tubulointerstitial damage is shown in D and H&E-stained histological images in E (n = 3/group). *P < 0.05. (F) KIM-1 immunostaining using Abs targeting the extracellular domain of KIM-1 and percentage of KIM-1+ cells in primary PTCs from KIM-1 and KIM-1Δmucin mice. Scale bar: 50 μm. (G) Percentage of Ki67+ primary PTCs from KIM-1 and KIM-1Δmucin mice over time in primary culture. (H) TUNEL in situ hybridization of PTCs after a 16-hour incubation with various doses of cisplatin. (I) LDH released from PTCs after exposure to H2O2 at various doses (n = 3). Statistical comparisons were calculated by ANOVA followed by Bonferroni’s post-hoc analysis. (F–I) No statistical differences between WT KIM-1 and KIM-1Δmucin groups.