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

J Clin Invest. 2015 Apr;125(4):1620-36. doi: 10.1172/JCI75417. Epub 2015 Mar 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cisplatin / toxicity
  • Cytokines / biosynthesis
  • Cytokines / metabolism
  • Epithelial Cells / metabolism
  • Extracellular Matrix Proteins
  • Gene Expression Regulation
  • Hepatitis A Virus Cellular Receptor 1
  • Homeodomain Proteins / genetics
  • Immunity, Innate
  • Inflammation
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Kidney / blood supply
  • Kidney Tubules, Proximal / metabolism
  • LLC-PK1 Cells
  • Macrophage Activation / genetics
  • Macrophage Activation / physiology*
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Phagocytosis / physiology*
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein Structure, Tertiary
  • Radiation Chimera
  • Reperfusion Injury / prevention & control
  • Swine


  • Cytokines
  • Ecm1 protein, mouse
  • Extracellular Matrix Proteins
  • Havcr1 protein, mouse
  • Hepatitis A Virus Cellular Receptor 1
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NF-kappa B
  • RAG-1 protein
  • Phosphatidylinositol 3-Kinases
  • Cisplatin