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Abstract: FR-PO255

Loss of Cross-Talk Between Polycystin 1 and LSD1 Promotes Cyst Growth Through Interaction With Ataxia Telangiectasia Mutated and Phase Separation Mechanism in Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Li, Xiaoyan, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Zhou, Xia, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Agborbesong, Ewud, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is caused by genetic mutations of PKD1/PKD2. Although diverse epigenetic regulators promote cyst growth in ADPKD through regulating cystic cell proliferation, apoptosis and ciliogenesis, and targeting dysregulated epigenetic regulators attenuates cyst growth in Pkd1 mutant mouse models, however, a direct connection between polycystin(s) and epigenetic mechanisms and how epigenetic regulators are regulated in ADPKD kidneys remain elusive.

Methods

To understand the role of lysine specific demethylase (LSD1) in cyst growth in vivo, we treated Pkd1nl/nl and Pkd1RC/RC mice with LSD1 specific inhibitor ORY-1001 (400 μg/kg) by intraperitoneally (IP) injection. To establish a direct interaction between polycystin 1 (PC1) and LSD1, and an interaction between LSD1 and ataxia telangiectasia mutated (ATM), we performed co-immunoprecipitation (Co-IP) assays in Pkd1 wildtype and mutant renal epithelial cells.

Results

We found that the expression of LSD1 was upregulated in kidneys in Pkd1 mutant mice and ADPKD patients and targeting LSD1 with its inhibitor delayed cyst growth as seen by decreased cystic index, kidney weight (KW)/body weight (BW) ratios, blood urea nitrogen (BUN) levels and cell proliferation, and increased cystic cell apoptosis in Pkd1 mutant mice (all p < 0.05). The molecular mechanisms of LSD1 in regulating cyst growth include: 1) the interaction with PC1, which decreases the stability and activity of LSD1 when PC1 is present, but loss of PC1 results in the upregulation of LSD1, 2) the interaction of LSD1 with its novel substrate, ATM to regulate the demethylation and activation of ATM, resulting in cyst growth in ADPKD kidneys, 3) the compositions of two intrinsic disordered regions (IDRs) in LSD1 amino acid sequence, suggesting the potential of LSD1 to form phase separation droplets, and 4) the formation of LSD1 phase separation droplets in cystic epithelial cells in kidneys from Pkd1 mutant mice and ADPKD patients but not in wild type tissues.

Conclusion

This is the first study, 1) to establish a direct association of PC1 with an epigenetic regulator LSD1 in renal epithelial cells, and 2) to identify that ATM is a novel substrate of LSD1 to promote DNA damage response. In addition, LSD1 mediated phase-separation also promotes cyst growth in ADPKD.

Funding

  • NIDDK Support