肌成纤维细胞
转分化
纤维化
硫氧化物9
生物
细胞生物学
肾
病理
医学
转录因子
癌症研究
内分泌学
干细胞
生物化学
基因
作者
Sayyid Raza,Elliot Jokl,James Pritchett,Katherine J. Martin,Kim Su,Kara Simpson,Lindsay Birchall,Aoibheann F. Mullan,Varinder Athwal,Daniel T. Doherty,Leo Zeef,Neil Henderson,Philip A. Kalra,Neil A. Hanley,Karen Hanley
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2021-03-02
卷期号:14 (672)
被引量:25
标识
DOI:10.1126/scisignal.abb4282
摘要
Renal fibrosis is a common end point for kidney injury and many chronic kidney diseases. Fibrogenesis depends on the sustained activation of myofibroblasts, which deposit the extracellular matrix that causes progressive scarring and organ failure. Here, we showed that the transcription factor SOX9 was associated with kidney fibrosis in humans and required for experimentally induced kidney fibrosis in mice. From genome-wide analysis, we identified Neuron navigator 3 (NAV3) as acting downstream of SOX9 in kidney fibrosis. NAV3 increased in abundance and colocalized with SOX9 after renal injury in mice, and both SOX9 and NAV3 were present in diseased human kidneys. In an in vitro model of renal pericyte transdifferentiation into myofibroblasts, we demonstrated that NAV3 was required for multiple aspects of fibrogenesis, including actin polymerization linked to cell migration and sustained activation of the mechanosensitive transcription factor YAP1. In summary, our work identifies a SOX9-NAV3-YAP1 axis involved in the progression of kidney fibrosis and points to NAV3 as a potential target for pharmacological intervention.
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