SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function

Sayyid Raza, Elliot Jokl, Jim Pritchett, Katherine Martin, Kimberley Su, Kara Simpson, Lindsay Birchall, Aoibheann Mullan, Varinder Athwal, Daniel Doherty, Leo Zeef, Neil Henderson, Philip Kalra, Neil Hanley, Karen Piper Hanley

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
JournalScience Signaling
Publication statusPublished - Feb 2021


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