KIM-1-mediated phagocytosis reduces acute injury to the kidney.
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.
Li
L
Yang
Craig R
CR
Brooks
Sheng
S
Xiao
Venkata
V
Sabbisetti
Melissa Y
MY
Yeung
Li-Li
LL
Hsiao
Takaharu
T
Ichimura
Vijay
V
Kuchroo
Joseph V
JV
Bonventre
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D005786:Gene Expression Regulation; D000072596:Hepatitis A Virus Cellular Receptor 1; D018398:Homeodomain Proteins / Q000235:genetics; D007113:Immunity, Innate; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism; D007668:Kidney / Q000098:blood supply; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D018374:LLC-PK1 Cells; D008262:Macrophage Activation / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017434:Protein Structure, Tertiary; D011828:Radiation Chimera; D015427:Reperfusion Injury / Q000517:prevention & control; D013552:Swine
D016207:Cytokines; C094556:Ecm1 protein, mouse; D016326:Extracellular Matrix Proteins; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; C064658:RAG-1 protein; D019869:Phosphatidylinositol 3-Kinases; D002945:Cisplatin