EGR1 Nuclear Condensates Promote Renal Cyst Development in Polycystic Kidney Disease

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is characterized by abnormal renal cyst epithelial cell proliferation.
• Aberrant cell proliferation in ADPKD is linked to cAMP-PKA and MAPK signaling pathways.
• Early growth response 1 (EGR1) is a transcription factor activated by these pathways and implicated in tumor cell proliferation.

Purpose of the Study:

• To investigate the role of Early growth response 1 (EGR1) in the development of renal cysts in Autosomal dominant polycystic kidney disease (ADPKD).
• To explore the mechanism by which EGR1 contributes to cyst enlargement and cell proliferation in ADPKD.

Main Methods:

• Utilized in vitro cell models, a 3D cyst model, an embryonic renal cystic model, and a Polycystic Kidney Disease (PKD) mouse model.
• Examined EGR1 expression and localization in human ADPKD and mouse kidney tissues.
• Investigated the effect of pharmacological EGR1 inhibition on cyst growth.
• Analyzed EGR1's interaction with YAP1 and CBP via phase separation and its impact on cell-cycle-related gene expression.

Main Results:

• High expression and nuclear condensates of EGR1 were observed in human ADPKD renal cyst epithelial cells and PKD mouse kidney tissues.
• Pharmacological inhibition of EGR1 significantly retarded cyst enlargement across various ADPKD models (in vitro, ex vivo, in vivo).
• EGR1 forms nuclear condensates with YAP1 and CBP through phase separation, driving the upregulation of cell-cycle genes (CCND1, CCNE1, CDK4/6) and promoting proliferation.
• Disrupting EGR1 phase separation markedly alleviated cyst growth in 3D spheroid and MDCK cyst models.

Conclusions:

• Phase separation-mediated EGR1 condensates play a crucial role in facilitating renal cyst development and enlargement in ADPKD.
• Targeting EGR1 phase separation presents a potential therapeutic strategy for mitigating cyst progression in ADPKD.