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

Loss of the transcription factor SOX9 reduces experimentally induced kidney fibrosis in mice. Stimulating renal fibrosis with SOX9 Chronic kidney diseases (CKDs) and kidney injuries often culminate in renal fibrosis and organ failure. Raza et al. identified a role for the transcription factor SOX9 in renal fibrosis. SOX9 and its potential direct target Neuron navigator 3 (Nav3) were present in fibrotic kidneys from patients with CKD. In mice, Sox9 deficiency reduced injury-induced kidney fibrosis and the associated increase in Nav3 expression. NAV3 was required for the transdifferentiation of primary mouse renal pericytes into fibrosis-promoting myofibroblasts and promoted cytoskeletal reorganization and mechanosignaling characteristic of myofibroblasts in cultured human and mouse renal cells. These findings implicate SOX9 and NAV3 in the progression of renal fibrosis and suggest pericytes as a potential source of myofibroblasts in renal fibrosis. 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.