CLEC14A protects against podocyte injury in mice with adriamycin nephropathy
CLEC14A protects against podocyte injury in mice with adriamycin nephropathy
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DOI：
10.1096/fj.202100283r
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发表时间：
2021-07
期刊：
影响因子：
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通讯作者：
Zeyu Su;Yujia Li;Hang Lv;Xiaoyang Cui;Min Liu;Ziying Wang;Yan Zhang;J. Zhen;Wei Tang;Xiaojie Wang;F. Yi
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文献类型：
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作者：
Zeyu Su;Yujia Li;Hang Lv;Xiaoyang Cui;Min Liu;Ziying Wang;Yan Zhang;J. Zhen;Wei Tang;Xiaojie Wang;F. Yi
足细胞损伤是局灶节段性肾小球硬化症（FSGS）的主要决定因素，识别预防足细胞损伤的潜在治疗靶点对于FSGS的治疗具有临床重要性。CLEC 14 A是一种单次跨膜糖蛋白，属于血管表达的C型凝集素家族。CLEC 14 A被发现在胚胎发生期间在血管内皮细胞中表达，并且还涉及肿瘤血管生成。然而，目前对CLEC 14 A在足细胞中的生物学功能的了解非常有限。在这项研究中，我们发现CLEC 14 A在足细胞中表达，并在阿霉素（ADR）诱导的FSGS小鼠中保护足细胞免受损伤。首先，我们观察到CLEC 14 A在ADR肾病小鼠和FSGS和其他形式足细胞病变个体的肾活检中下调。此外，CLEC 14 A缺陷加重了ADR肾病小鼠的足细胞损伤和蛋白尿，伴随着增强的炎性细胞浸润和炎症反应。在体外，CLEC 14 A在足细胞中的过表达具有多效性保护作用，包括抗炎和抗凋亡作用。CLEC 14 A至少部分通过直接结合高迁移率族蛋白1（HMGB 1）来抑制HMGB 1的释放，并抑制HMGB 1介导的信号传导，包括NF-κB信号传导和早期生长反应蛋白1（EGFR 1）信号传导。总之，我们的研究结果为CLEC 14 A在维持足细胞功能中的关键作用提供了新的见解，表明CLEC 14 A可能是FSGS的创新治疗靶点。
Podocyte injury is a major determinant of focal segmental glomerular sclerosis (FSGS) and the identification of potential therapeutic targets for preventing podocyte injury has clinical importance for the treatment of FSGS. CLEC14A is a single‐pass transmembrane glycoprotein belonging to the vascular expressed C‐type lectin family. CLEC14A is found to be expressed in vascular endothelial cells during embryogenesis and is also implicated in tumor angiogenesis. However, the current understanding of the biological functions of CLEC14A in podocyte is very limited. In this study, we found that CLEC14A was expressed in podocyte and protected against podocyte injury in mice with Adriamycin (ADR)‐induced FSGS. First, we observed that CLEC14A was downregulated in mice with ADR nephropathy and renal biopsies from individuals with FSGS and other forms of podocytopathies. Moreover, CLEC14A deficiency exacerbated podocyte injury and proteinuria in mice with ADR nephropathy accompanied by enhanced inflammatory cell infiltration and inflammatory responses. In vitro, overexpression of CLEC14A in podocyte had pleiotropic protective actions, including anti‐inflammatory and anti‐apoptosis effects. Mechanistically, CLEC14A inhibited high‐mobility group box 1 protein (HMGB1) release, at least in part by directly binding HMGB1, and suppressed HMGB1‐mediated signaling, including NF‐κB signaling and early growth response protein 1 (EGR1) signaling. Taken together, our findings provide new insights into the pivotal role of CLEC14A in maintaining podocyte function, indicating that CLEC14A may be an innovative therapeutic target in FSGS.