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

Yang L, Brooks CR, Xiao S, Sabbisetti V, Yeung MY, Hsiao LL, Ichimura T, Kuchroo V, Bonventre JV
J Clin Invest. 2015 125 (4): 1620-36

PMID: 25751064 · PMCID: PMC4396492 · DOI:10.1172/JCI75417

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.

MeSH Terms (29)

Acute Kidney Injury Animals Apoptosis Cisplatin Cytokines Epithelial Cells Extracellular Matrix Proteins Gene Expression Regulation Hepatitis A Virus Cellular Receptor 1 Homeodomain Proteins Immunity, Innate Inflammation Intercellular Signaling Peptides and Proteins Kidney Kidney Tubules, Proximal LLC-PK1 Cells Macrophage Activation Male Membrane Proteins Mice Mice, Inbred C57BL Mice, Knockout NF-kappa B Phagocytosis Phosphatidylinositol 3-Kinases Protein Structure, Tertiary Radiation Chimera Reperfusion Injury Swine

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