Athwal, Varinder

Birchall, Lindsay

Doherty, Daniel

Hanley, Neil

Henderson, Neil

Jokl, Elliot

Kalra, Philip

Martin, Katherine

Mullan, Aoibheann

Piper Hanley, Karen

Pritchett, Jim

Raza, Sayyid

Simpson, Kara

Su, Kimberley

Zeef, Leo

Renal fibrosis is a common end point for kidney injury and many chronic kidney diseases. Fibrogenesis dependson the sustained activation of myofibroblasts, which deposit the extracellular matrix that causes progressive scarringand organ failure. Here, we showed that the transcription factor SOX9 was associated with kidney fibrosis in humansand required for experimentally induced kidney fibrosis in mice. From genome-wide analysis, we identified Neuronnavigator 3 (NAV3) as acting downstream of SOX9 in kidney fibrosis. NAV3 increased in abundance and colocalizedwith SOX9 after renal injury in mice, and both SOX9 and NAV3 were present in diseased human kidneys. In an in vitromodel of renal pericyte transdifferentiation into myofibroblasts, we demonstrated that NAV3 was required formultiple aspects of fibrogenesis, including actin polymerization linked to cell migration and sustained activation ofthe mechanosensitive transcription factor YAP1. In summary, our work identifies a SOX9-NAV3-YAP1 axis involvedin the progression of kidney fibrosis and points to NAV3 as a potential target for pharmacological intervention

The University of Manchester - Institutional Repository

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

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

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The University of Manchester - Institutional Repository