Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta‐like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1‐null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey‐1 expression compared to wild‐type (WT) littermates. NOTCH1 over‐activation in Dlk1‐null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL‐17A and other related‐inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non‐canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17‐mediated inflammatory response.

中文翻译：

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删除 delta-like 1 同源物通过调节 Th17 免疫反应加速肾脏炎症

临床前研究表明，NOTCH 通路的激活在肾损伤的发病机制中起关键作用。目前没有关于 Delta 样同源物 1（DLK1）（一种 NOTCH 抑制剂）在调节肾损伤中的作用的信息。在这里，我们研究了 DLK1 对实验性肾损伤的贡献和潜在的分子机制。在单侧输尿管梗阻的实验性肾损伤中使用 Dlk1-null 小鼠模型，我们发现 NOTCH 激活，如与野生型相比，NOTCH1 细胞内结构域的核易位增加和 Dlk2/hey-1 表达上调所示。 WT）同窝仔。在 Dlk1 缺失的受损肾脏中，NOTCH1 过度激活与更高的炎症反应有关，其特征是炎症细胞的浸润，主要是 CD4/IL17A + 淋巴细胞，激活 Th17 免疫反应。此外，药理学 NOTCH 阻断抑制了控制 Th17 分化和 Th17 效应细胞因子 IL-17A 和其他相关炎症因子的基因表达的转录因子，这与受损肾脏炎症的减轻有关。我们提出非经典 NOTCH 配体 DLK1 在肾损伤中作为 NOTCH 拮抗剂调节 Th17 介导的炎症反应。