Podocyte-specific YAP activation triggers crescentic glomerulonephritis through cross-talk with parietal epithelial...

Crescentic glomerulonephritis (cGN) is a severe kidney pathology characterized by the aberrant proliferation of epithelial cells, leading to crescent formation within the Bowman's space. The molecular pathways involved in crescent formation remain poorly understood despite its clinical relevance. Given the mechanical stress experienced by podocytes, likely exacerbated in cGN, we hypothesized that activation of the mechanosensor yes-associated protein 1 (YAP), an effector of the Hippo pathway, may contribute to the development of cGN. Here, we demonstrate activation of YAP and its target genes in the nephrotoxic nephritis model, a murine model of cGN. Mechanistically, podocyte-specific hyperactivation of YAP (YAP^5SA) in transgenic mice led to cell-autonomous hypertrophy of podocytes and non-cell-autonomous activation and proliferation of parietal epithelial cells (PECs), culminating in crescents. Transcriptomic profiling in a human podocyte cell line expressing the same YAP^5SA isoform revealed the reactivation of developmental programs within differentiated podocytes and identified the phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin (PI3K-Akt-mTOR) signaling pathway as a candidate involved in YAP-induced podocyte hypertrophy. Furthermore, this analysis identified connective tissue growth factor (CTGF) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) as potential mediators in the cross-talk between YAP-activated podocytes and PECs, driving PEC hyperplasia. Collectively, these findings highlight the pivotal role of YAP in the pathogenesis of cGN and indicate that targeting YAP signaling could be a promising therapeutic strategy for this severe kidney disease.