SOX9 is required for kidney fibrosis and regulates NAV3 to control renal myofibroblast function in mice and humans

Renal fibrosis is a common endpoint for many chronic kidney diseases. Extracellular matrix (ECM) from myofibroblasts causes progressive scarring and organ failure. The mechanisms underlying fibrogenesis and how it is sustained are incompletely understood. Here, we show that the transcription factor, Sex determining region Y-box 9 (SOX9), is required for kidney fibrosis. From genome-wide analysis we identify Neuron navigator 3 (NAV3) downstream of SOX9. NAV3 was upregulated in kidney disease in patients and following renal injury in mice colocalised with SOX9. By establishing an in vitro model of renal pericyte transition to myofibroblast we demonstrated that NAV3 is required for multiple aspects of fibrogenesis including actin polymerization linked to cell migration and sustaining SOX9 and active YAP1 levels. In summary, our work discovers novel SOX9-NAV3-YAP1/SOX9 circuitry as a new mechanism to explain the progression of kidney fibrosis and points to NAV3 as a novel target for pharmacological intervention.