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 6

Expression of functional KIM-1 downmodulates inflammatory cytokine production by kidney epithelial cells.

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Expression of functional KIM-1 downmodulates inflammatory cytokine produ...
(A) Tlr4 mRNA levels in tubules isolated from KIM-1 (WT) and KIM-1Δmucin I/R-injured kidneys 1 and 3 days after injury (n = 3 mice/time point/group). *P < 0.05 vs. sham; #P < 0.05 vs. WT. (B) Tlr4 and Myd88 mRNA levels in primary cultured tubular cells isolated from KIM-1 and KIM-1Δmucin kidneys. *P < 0.01. (C) Coimmunostaining for KIM-1 (red) and TLR4 (green) in primary cultured tubular cells isolated from KIM-1 or KIM-1Δmucin mouse kidneys after exposure to LPS. WT KIM-1–expressing cells did not show obvious TLR4 expression, whereas KIM-1Δmucin–expressing cells showed increased intracellular TLR4 expression (images are representative of 3 independent experiments). Scale bar: 20 μm. (D) Secretion of IL-6 and RANTES by primary cultured tubular cells isolated from KIM-1 WT and KIM-1Δmucin kidneys. **P < 0.001; #P < 0.05 (n = 3). (E) Tlr4 mRNA levels in LLC-PK1 cells transfected with pCDH empty vector, WT KIM-1, or KIM-1Δmucin (n = 5). With LPS treatment, the pCDH cells had increased Tlr4 gene production, which did not change with apoptotic cell (APO) pre-feeding. Pre-feeding apoptotic cells to LLC-PK1 cells expressing WT KIM-1, but not KIM-1Δmucin, markedly decreased Tlr4 mRNA levels. *P < 0.01 and #P < 0.05. Statistical comparisons among groups were calculated by ANOVA followed by Bonferroni’s post-hoc analysis.