KIM-1-mediated anti-inflammatory activity is preserved by MUC1 induction in the proximal tubule during ischemia-reperfusion injury
KIM-1-mediated anti-inflammatory activity is preserved by MUC1 induction in the proximal tubule during ischemia-reperfusion injury
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DOI：
10.1152/ajprenal.00127.2021
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发表时间：
2021-08-01
影响因子：
4.2
通讯作者：
Hughey, Rebecca P.
中科院分区：
文献类型：
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作者：
Al-bataineh, Mohammad M.;Kinlough, Carol L.;Hughey, Rebecca P.
细胞相关肾损伤分子-1（KIM-1）通过介导红细胞增多和下调NF-κ B通路发挥肾损伤后的抗炎作用。KIM-1裂解减弱了其抗炎活性。我们报道了粘蛋白1（MUC 1）在小鼠缺血再灌注损伤（IRI）模型中具有保护作用。由于KIM-1和MUC 1在IRI期间在近端小管（PT）中被诱导，并且是去整合素和金属蛋白酶17（ADAM 17）底物，我们测试了MUC 1保护KIM-1活性的假设。对Muc 1敲除（KO）小鼠和野生型（WT）同窝小鼠进行IRI。通过免疫印迹分析评估KIM-1、MUC 1和ADAM 17水平（和信号传导途径）。通过共聚焦显微镜和原位邻位连接试验评估PT定位。在小鼠PT培养物中使用人肾脏和尿液以及KIM-1介导的红细胞增多试验扩展了发现。在小鼠和人类肾脏中，我们观察到肾小管损伤诱导和共表达KIM-1和MUC 1的PT。与WT小鼠相比，Muc 1 KO小鼠具有较高的尿KIM-1和较低的肾KIM-1。KIM-1在WT肾脏PT中位于顶端，但在Muc 1 KO小鼠中主要与管腔碎片一起。与WT培养物相比，Muc 1 KO PT培养物中的胞饮作用减少，而与WT肾脏相比，Muc 1 KO肾脏中的炎症增加。MUC 1在PT培养物中被ADAM 17切割，并在Madin-Darby犬肾细胞中阻断KIM-1脱落。我们的结论是，在IRI期间，通过MUC 1抑制KIM-1脱落，KIM-1介导的红细胞增多和抗炎活性在损伤的肾脏中得以保留。新&值得注意的是，KIM-1通过介导红细胞增多和抑制炎症的相关信号传导，在肾脏IRI期间肾小管上皮的恢复中起关键作用。KIM-1被ADAM 17过度切割提供了一种诱饵受体，其抑制了红细胞增多和随后的信号传导。我们在小鼠、患者和培养细胞中进行的实验数据表明，MUC 1也在IRI期间被诱导，并与KIM-1竞争ADAM 17的切割。因此，MUC 1保护受损肾脏中的KIM-1抗炎活性。
Cell-associated kidney injury molecule-1 (KIM-1) exerts an anti-inflammatory role following kidney injury by mediating efferocytosis and downregulating the NF-kappa B pathway. KIM-1 cleavage blunts its anti-inflammatory activities. We reported that mucin 1 (MUC1) is protective in a mouse model of ischemia-reperfusion injury (IRI). As both KIM-1 and MUC1 are induced in the proximal tubule (PT) during IRI and are a disintegrin and metalloprotease 17 (ADAM17) substrates, we tested the hypothesis that MUC1 protects KIM-1 activity. Muc1 knockout (KO) mice and wild-type (WT) littermates were subjected to IRI. KIM-1, MUC1, and ADAM17 levels (and signaling pathways) were assessed by immunoblot analysis. PT localization was assessed by confocal microscopy and an in situ proximity ligation assay. Findings were extended using human kidneys and urine as well as KIM-1-mediated efferocytosis assays in mouse PT cultures. In response to tubular injury in mouse and human kidneys, we observed induction and coexpression of KIM-1 and MUC1 in the PT. Compared with WT mice, Muc1 KO mice had higher urinary KIM-1 and lower kidney KIM-1. KIM-1 was apical in the PT of WT kidneys but predominately with luminal debris in Muc1 KO mice. Efferocytosis was reduced in Muc1 KO PT cultures compared with WT cultures, whereas inflammation was increased in Muc1 KO kidneys compared with WT kidneys. MUC1 was cleaved by ADAM17 in PT cultures and blocked KIM-1 shedding in Madin-Darby canine kidney cells. We conclude that KIM-1-mediated efferocytosis and thus anti-inflammatory activity during IRI is preserved in the injured kidney by MUC1 inhibition of KIM-1 shedding.NEW & NOTEWORTHY KIM-1 plays a key role in the recovery of the tubule epithelium during renal IRI by mediating efferocytosis and associated signaling that suppresses inflammation. Excessive cleavage of KIM-1 by ADAM17 provides a decoy receptor that aggravates efferocytosis and subsequent signaling. Our data from experiments in mice, patients, and cultured cells show that MUC1 is also induced during IRI and competes with KIM-1 for cleavage by ADAM17. Consequently, MUC1 protects KIM-1 anti-inflammatory activity in the damaged kidney.