尿调节蛋白p.His36Tyr通过App-Cd74信号传导促进巨噬细胞焦亡，从而驱动ADTKD中的肾脏炎症
Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD.
摘要(中文译文)
常染色体显性遗传性肾小管间质性肾病-UMOD的特征是进行性肾间质炎症和纤维化。然而，其潜在机制仍不清楚。在此，我们鉴定了一个携带新型UMOD p.H36Y突变的大型ADTKD家系。利用CRISPR/Cas9技术，我们构建了Umod小鼠模型，该模型重现了患病个体中观察到的关键表型，包括肾功能障碍、囊肿形成和间质炎症。对雄性Umod小鼠肾脏的多组学分析揭示了显著的巨噬细胞焦亡。在机制上，Umod p.H36Y变异激活了淀粉样前体蛋白（App）-Cd74轴，该轴介导了肾脏突变型肾小管细胞与巨噬细胞之间的串扰。该轴维持巨噬细胞中NF-κB通路的持续激活，启动焦亡并释放促炎细胞因子。同样的机制在UMOD p.Trp31Cys细胞模型中也得到了重现。值得注意的是，使用ARN2966（一种小分子App抑制剂）进行药理学抑制可减轻雄性Umod小鼠的肾损伤。总之，这些发现揭示了ADTKD-UMOD中一条可靶向的通路。
Abstract
Autosomal dominant tubulointerstitial kidney disease -UMOD is characterized by progressive renal interstitial inflammation and fibrosis. However, its underlying mechanisms remain unclear. Here, we identify a large ADTKD pedigree harboring a novel UMOD p.H36Y mutation. Using CRISPR/Cas9 technology, we generated a Umod mouse model that recapitulates the key phenotypes observed in affected individuals, including renal dysfunction, cyst formation, and interstitial inflammation. Multi-omics analyses in kidneys from male Umod mice revealed marked macrophage pyroptosis. Mechanistically, the Umod p.H36Y variant activated the amyloid precursor protein (App)-Cd74 axis which mediated the crosstalk between renal mutant tubular cells and macrophages. This axis sustains NF-κB pathway activation in macrophages, initiating pyroptosis and pro-inflammatory cytokine release. The same mechanism is recapitulated in the UMOD p.Trp31Cys cell model. Notably, Pharmacologic inhibition using ARN2966, a small-molecule App inhibitor, attenuated renal injury in male Umod mice. Collectively, these findings uncover a targetable pathway in ADTKD-UMOD.
如何引用
AMA
Qian-Qian Wu, Si-Qi Peng, Yi-Lin Zhang, Yan Yang, Wen Shi, Xian-Li Wen, et al. Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD.. Nature communications. 2026; doi:10.1038/s41467-026-72451-3.
APA
Qian-Qian Wu, Si-Qi Peng, Yi-Lin Zhang, Yan Yang, Wen Shi, Xian-Li Wen, et al (2026). Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD.. Nature communications. https://doi.org/10.1038/s41467-026-72451-3
GB/T 7714
Qian-Qian Wu, Si-Qi Peng, Yi-Lin Zhang, Yan Yang, Wen Shi, Xian-Li Wen, et al. Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD.[J]. Nature communications, 2026 doi:10.1038/s41467-026-72451-3.
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