Scholarlink

<p>Autosomal dominant tubulointerstitial kidney disease -<i>UMOD</i> 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 <i>UMOD</i> p.H36Y mutation. Using CRISPR/Cas9 technology, we generated a <i>Umod</i><sup>H36Y/+</sup> 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 <i>Umod</i><sup>H36Y/+</sup> mice revealed marked macrophage pyroptosis. Mechanistically, the <i>Umod</i> 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 <i>UMOD</i> p.Trp31Cys cell model. Notably, Pharmacologic inhibition using ARN2966, a small-molecule App inhibitor, attenuated renal injury in male <i>Umod</i><sup>H36Y/+</sup> mice. Collectively, these findings uncover a targetable pathway in ADTKD-<i>UMOD</i>.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月29日

查看全文
  • Qian-Qian Wu,
  • Si-Qi Peng,
  • Yi-Lin Zhang,
  • Yan Yang,
  • Wen Shi,
  • Xian-Li Wen,
  • Zhi-Ying Liu,
  • Xu-Jie Zhou,
  • Ming-Zhu Zheng,
  • Li-Dan Hu,
  • Xiao-Min Li,
  • Jing-Yuan Cao,
  • Xin-Lu Wang,
  • Jun-Lan Yang,
  • Jin-Xuan Wei,
  • Jun-Yuan Shen,
  • Xiao-Xu Wang,
  • Bi-Cheng Liu,
  • Xiao-Liang Zhang,
  • Bin Wang

摘要

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 UmodH36Y/+ 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 UmodH36Y/+ 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 UmodH36Y/+ mice. Collectively, these findings uncover a targetable pathway in ADTKD-UMOD.