PDF(Pubmed)
Abstract：
Elevated interferon (IFN) signaling is associated with kidney diseases including COVID-19, HIV, and apolipoprotein-L1 (APOL1) nephropathy, but whether IFNs directly contribute to nephrotoxicity remains unclear. Using human kidney organoids, primary endothelial cells, and patient samples, we demonstrate that IFN-γ induces pyroptotic angiopathy in combination with APOL1 expression. Single-cell RNA sequencing, immunoblotting, and quantitative fluorescence-based assays reveal that IFN-γ-mediated expression of APOL1 is accompanied by pyroptotic endothelial network degradation in organoids. Pharmacological blockade of IFN-γ signaling inhibits APOL1 expression, prevents upregulation of pyroptosis-associated genes, and rescues vascular networks. Multiomic analyses in patients with COVID-19, proteinuric kidney disease, and collapsing glomerulopathy similarly demonstrate increased IFN signaling and pyroptosis-associated gene expression correlating with accelerated renal disease progression. Our results reveal that IFN-γ signaling simultaneously induces endothelial injury and primes renal cells for pyroptosis, suggesting a combinatorial mechanism for APOL1-mediated collapsing glomerulopathy, which can be targeted therapeutically.
摘要：
干扰素（IFN）信号升高与肾脏疾病相关，包括COVID-19，HIV，和载脂蛋白-L1（APOL1）肾病，但IFN是否直接导致肾毒性尚不清楚.使用人类肾脏类器官，原代内皮细胞，和病人样本，我们证明了IFN-γ与APOL1表达结合可诱导变性血管病变。单细胞RNA测序，免疫印迹,和基于荧光的定量测定表明，IFN-γ介导的APOL1表达伴随着类器官中的热解内皮细胞网络降解。IFN-γ信号传导的药理学阻断抑制APOL1表达，防止焦亡相关基因的上调，并拯救血管网络。COVID-19，蛋白尿肾病，和萎缩性肾小球病同样表明IFN信号和焦亡相关基因表达增加与肾脏疾病进展加速相关。我们的结果表明，IFN-γ信号同时诱导内皮损伤和启动肾细胞的焦亡，提示APOL1介导的塌陷性肾小球病的组合机制，可以有针对性的治疗。
