Podocyte YAP and TAZ hyperactivation drives glomerular epithelial proliferative diseases in mice and humans.

Kidney diseases characterized by glomerular epithelial cell proliferation are rare but often devastating, frequently leading to progressive scarring and renal failure. Ranging from autoimmune-induced crescentic glomerulonephritis to HIV infection-induced collapsing glomerulopathy, these diseases are triggered by a wide variety of insults and have generally been thought of as different entities. Here, using immunostaining and spatial transcriptomics, we profiled human kidney biopsies collected from patients with two of these diseases, collapsing glomerulopathy and antineutrophil cytoplasmic antibody (ANCA) vasculitis-induced crescentic glomerulonephritis, to identify common disease-causing molecules. Although triggered by different insults, we identified abnormal hyperactivation of the transcription cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in podocytes as a potential common driver of these diseases. To test this hypothesis, we genetically activated podocyte YAP and TAZ in cultured human cells and in mice by deleting the YAP and TAZ inhibitory large tumor suppressor kinases (LATSs). LATS deficiency in mouse podocytes induced a phenotypic transition in vitro, characterized by a highly distorted structure and an increase in matrix gene expression, mimicking many features of the podocytopathy seen in diseases characterized by glomerular epithelial proliferation. In mice, LATS-deficient podocytes orchestrated a profibrotic and pro-proliferative response in surrounding glomerular cells, a characteristic phenomenon of glomerular epithelial proliferative diseases. This response was attenuated when we also deleted podocyte YAP or TAZ in these mice. Together, our findings point to podocyte YAP-TAZ hyperactivation as a previously unrecognized and unifying driver of glomerular epithelial proliferative diseases.