NLRC5 deficiency protects against acute kidney injury in mice by mediating carcinoembryonic antigen-related cell adhesion molecule 1 signaling
NLRC5 deficiency protects against acute kidney injury in mice by mediating carcinoembryonic antigen-related cell adhesion molecule 1 signaling
复制标题
NLRC5缺陷通过介导癌胚抗原相关细胞粘附分子1信号传导来预防小鼠急性肾损伤
DOI：
10.1016/j.kint.2018.02.031
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发表时间：
2018-09-01
影响因子：
19.6
通讯作者：
Yi, Fan
中科院分区：
文献类型：
--
作者：
Li, Quanxin;Wang, Ziying;Yi, Fan
核苷酸寡聚化结构域样受体家族成员NLRC 5的结构和功能的研究取得了重大进展。然而，在MHC I类基因表达的背景下，NLRC 5在先天性和适应性免疫应答中的功能超出了MHC I类基因的调节仍然存在争议和未解决的问题。特别是，NLRC 5在肾脏中的作用是未知的。NLRC 5在肾缺血/再灌注损伤小鼠的肾脏中显著上调。与野生型小鼠相比，NLRC 5缺陷小鼠显着改善了肾损伤，这一点可以通过血清肌酸酐水平降低、形态损伤改善和炎症反应减少来证明。在顺铂诱导的急性肾损伤中也观察到类似的保护作用。从机制上讲，NLRC 5通过促进肾小管上皮细胞凋亡和减少炎症反应而导致肾损伤，至少部分与癌胚抗原相关细胞粘附分子1（CEACAM 1）的负调节有关。为了确定缺血/再灌注损伤期间实质细胞或白细胞表达NLRC 5对肾损伤的相对贡献，我们产生了骨髓嵌合小鼠。与用NLRC 5缺陷型骨髓重建的野生型小鼠相比，用野生型造血细胞移植的NLRC 5缺陷型小鼠具有显著更低的血清肌酐和更少的肾小管损伤。这表明肾实质细胞中的NLRC 5信号传导在介导肾损伤中起主导作用。因此，调节NLRC 5介导的通路可能对急性肾损伤患者具有重要的治疗意义。
There is significant progress in understanding the structure and function of NLRC5, a member of the nucleotide oligomerization domain-like receptor family. However, in the context of MHC class I gene expression, the functions of NLRC5 in innate and adaptive immune responses beyond the regulation of MHC class I genes remain controversial and unresolved. In particular, the role of NLRC5 in the kidney is unknown. NLRC5 was significantly upregulated in the kidney from mice with renal ischemia/reperfusion injury. NLRC5 deficient mice significantly ameliorated renal injury as evidenced by decreased serum creatinine levels, improved morphological injuries, and reduced inflammatory responses versus wild type mice. Similar protective effects were also observed in cisplatin-induced acute kidney injury. Mechanistically, NLRC5 contributed to renal injury by promoting tubular epithelial cell apoptosis and reducing inflammatory responses were, at least in part, associated with the negative regulation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). To determine the relative contribution of NLRC5 expression by parenchymal cells or leukocytes to renal damage during ischemia/reperfusion injury, we generated bone marrow chimeric mice. NLRC5 deficient mice engrafted with wild type hematopoietic cells had significantly lower serum creatinine and less tubular damage than wild type mice reconstituted with NLRC5 deficient bone marrow. This suggests that NLRC5 signaling in renal parenchymal cells plays the dominant role in mediating renal damage. Thus, modulation of the NLRC5-mediated pathway may have important therapeutic implications for patients with acute kidney injury.