Hyperactivation of YAP/TAZ Drives Alterations in Mesangial Cells through Stabilization of N-Myc in Diabetic Nephropathy

Abstract

Significance statement: Mesangial cells (MCs) in the kidney are essential to maintaining glomerular integrity, and their impairment leads to major glomerular diseases including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying mechanism is poorly understood. We show that YAP/TAZ are increased in MCs of patients with DN and two animal models of DN. High glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse MCs recapitulates the hallmarks of DN. Activated YAP/TAZ bind and stabilize N-Myc, one of the Myc family. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and to MC impairments. Our findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis.

Background: Mesangial cells (MCs) in the kidney are central to maintaining glomerular integrity, and their impairment leads to major glomerular diseases, including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying molecular mechanism is poorly understood.

Methods: Immunolocalization of YAP/TAZ and pathological features of PDGFRβ + MCs were analyzed in the glomeruli of patients with DN, in Zucker diabetic fatty rats, and in Lats1/2i ΔPβ mice. RiboTag bulk-RNA sequencing and transcriptomic analysis of gene expression profiles of the isolated MCs from control and Lats1/2iΔPβ mice were performed. Immunoprecipitation analysis and protein stability of N-Myc were performed by the standard protocols.

Results: YAP and TAZ, the final effectors of the Hippo pathway, are highly increased in MCs of patients with DN and in Zucker diabetic fatty rats. Moreover, high glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse model MCs recapitulates the hallmarks of DN, including excessive proliferation of MCs and extracellular matrix deposition, endothelial cell impairment, glomerular sclerosis, albuminuria, and reduced glomerular filtration rate. Mechanistically, activated YAP/TAZ bind and stabilize N-Myc protein, one of the Myc family of oncogenes. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and eventually to MC impairments and DN pathogenesis.

Conclusions: Our findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis.