Identifying the role of YAP/TAZ and N-MYC in mesangial expansion

Abstract

Mesangial cells (MCs) are essential for maintaining glomerular homeostasis and play a critical role in initiation and progression of glomerular disease. However, it remains unclear how the MCs are regulated under pathologic conditions. Here, we show that selective hyperactivation of YAP/TAZ in PDGFRβ+ MCs results in dedifferentiation into myofibroblast, which leads to mesangial cell proliferation and mesangial fibrosis. In addition, mesangial expansion induces impairment of glomerular vascular barriers and loss of glomerular filtration function. Furthermore, transcriptomic and biochemical analyses reveal that YAP/TAZ and N-MYC interaction is required for development of mesangial expansion. YAP/TAZ adjust the half-life of N-MYC to cause MC proliferation and following fibrosis. Together, our findings demonstrate the molecular significance of YAP/TAZ and N-MYC in mesangial cell dedifferentiation and fibrosis, providing the insight to describe regulatory mechanisms under glomerular sclerosis.