KIM-1-mediated phagocytosis reduces acute injury to the kidney
KIM-1-mediated phagocytosis reduces acute injury to the kidney
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KIM-1 介导的吞噬作用可减少肾脏的急性损伤
DOI：
10.1172/jci75417
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发表时间：
2015-04-01
影响因子：
15.9
通讯作者：
Bonventre, Joseph V.
中科院分区：
文献类型：
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作者：
Yang, Li;Brooks, Craig R.;Bonventre, Joseph V.
肾损伤分子1（KIM-1，也称为TIM-1）在损伤后在近端小管中显著上调，并且当慢性表达时是适应不良的。在这里，我们确定在损伤过程的早期，KIM-1的表达是不稳定的，这是由于它介导了小管细胞中的吞噬过程。使用各种急性肾损伤（阿基）模型和表达KIM-1突变形式的小鼠，我们证明了上皮KIM-1表达的粘蛋白结构域依赖性保护作用，涉及先天免疫的下调。粘蛋白结构域的缺失显著损害KIM-1介导的吞噬功能，导致促炎细胞因子产生增加，近端上皮细胞的促生长因子分泌减少，随后组织巨噬细胞增加。表达KIM-1（δ粘蛋白）的小鼠在缺血和顺铂诱导的阿基中具有更大的功能障碍、炎症反应和死亡率。与从KIM-1（Delta粘蛋白）小鼠分离的原代肾近端小管细胞相比，来自WT小鼠的原代肾近端小管细胞具有减少的促炎细胞因子分泌和受损的巨噬细胞活化。KIM-1表达的抑制作用是由于KIM-1与p85的相互作用以及随后NF-κ B的PI 3 K依赖性下调。因此，KIM-1介导的上皮细胞吞噬凋亡细胞通过下调先天免疫和炎症来保护急性损伤后的肾脏。
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-1(Delta mucin) 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-1(Delta mucin) 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-kappa B. Hence, KIM-1-mediated epithelial cell phagocytosis of apoptotic cells protects the kidney after acute injury by downregulating innate immunity and inflammation.