EGR1 Nuclear Condensates Promote Renal Cyst Development in Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is marked by aberrant cell proliferation driven by cAMP-PKA and MAPK signaling pathways. EGR1, a transcription factor directly activated by the above two pathways, is critical in the over-proliferation of tumor cells, which share similarities with cystic epithelial cells in ADPKD. This study utilized in vitro cell models, three-dimensional (3D) cyst model, embryonic renal cystic model, and PKD mouse model to clarify the role of EGR1 in cyst development of ADPKD. We found the high expression and nuclear condensates of EGR1 in human ADPKD renal cyst epithelial cells and PKD mouse kidney tissue. Pharmacological inhibition of EGR1 retarded cyst enlargement in in vitro, ex vivo, and in vivo ADPKD models. Furthermore, EGR1 formed nuclear condensates with YAP1 and CBP via phase separation, leading to EGR1-specific transcriptional activation and upregulation of cell-cycle-related genes (e.g., CCND1, CCNE1, and CDK4/6), thus promoting abnormal renal cystic epithelial cell proliferation. Disruption of EGR1 phase separation significantly alleviated cyst growth in the forskolin-induced 3D spheroid model of mIMCD3 cells and MDCK cyst model. These findings demonstrate that phase separation-mediated EGR1 condensates facilitate renal cyst development in ADPKD.