Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1 + ) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1 + cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1 + cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell–resolution transcriptomic analysis, we identified an “inflammatory” proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)–induced IHH production in vivo. TNF-induced Ubiquitin D ( Ubd ) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1 + cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8 -expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1 + cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.

中文翻译：

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印度刺猬从 TNF 激活的肾上皮细胞中释放驱动局部和远端器官纤维化


进行性纤维化是包括肾脏和心脏在内的多个器官的衰老和慢性组织损伤的一个特征。胶质瘤相关癌基因 1 表达 (Gli1 + ) 细胞是多个器官中活化成纤维细胞的主要来源，但损伤、炎症和 Gli1 之间的联系+细胞扩张和组织纤维化仍不完全清楚。我们证明白细胞源性肿瘤坏死因子 (TNF) 促进 Gli1 +通过肾上皮细胞诱导和释放 Indian Hedgehog (IHH) 来促进细胞增殖和心肾纤维化。通过单细胞分辨率转录组分析，我们发现了一个“炎症”近端肾小管上皮 (iPT) 群体，该群体有助于 TNF 和核因子 κB (NF-κB) 诱导体内 IHH 的产生。 TNF 诱导的泛素 D（乌布德) 在体外人近端肾小管细胞中以及在小鼠和人类肾脏疾病和衰老过程中观察到表达。使用 TNF 诱导的 IHH 信号传导的药理学和条件遗传消除的研究表明，IHH 激活了 Gli1 中的经典 Hedgehog 信号传导+细胞，导致受损和老化的肾脏和心脏内的细胞活化、增殖和纤维化。这些变化在小鼠体内被抑制呃删除于8人-表达细胞或通过药物阻断 TNF、NF-κB 或 Gli1 信号传导。循环 IHH 量的增加与慢性肾病患者的肾功能丧失和心血管疾病发生率较高有关。 因此，IHH 将白细胞激活与 Gli1 连接起来+细胞扩张，并代表了抑制炎症诱导的纤维化治疗的潜在靶点。