Journal
SCIENCE SIGNALING
Volume 14, Issue 672, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.abb4282
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Categories
Funding
- Medical Research Council (MRC) [MR/J003352/1, MR/P023541/1, MR/000638/1, MR/S036121/1]
- NIHR
- Wellcome
- KRUK Clinical Training Fellowship
- IUK [40896]
- Wellcome Trust [105610]
- Kidneys for Life
- MRC [MR/S036121/1, MR/N025989/1, MR/P023541/1] Funding Source: UKRI
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This study identified a SOX9-NAV3-YAP1 axis involved in the progression of kidney fibrosis and suggested that NAV3 could be a potential target for pharmacological intervention.
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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