Kidney Week

Abstract: PO1247

Beneficial Effects of Bempedoic Acid Treatment in ADPKD Mice

Session Information

• Cystic Kidney Disease - I
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Hallows, Kenneth R., University of Southern California Keck School of Medicine, Los Angeles, California, United States

Kenneth R. Hallows, MD, PhD, FASN

• Li, Hui, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Hui Li,

• Saitta, Biagio, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Biagio Saitta,

• Sepehr, Saman, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Saman Sepehr,

• Pham, Jessica, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Jessica Pham,

• Mancino, Valeria, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Valeria Mancino,

• Pinkosky, Stephen L., Esperion Therapeutics Inc, Ann Arbor, Michigan, United States

Stephen L. Pinkosky,

• Pastor-Soler, Nuria M., University of Southern California Keck School of Medicine, Los Angeles, California, United States

Nuria M. Pastor-Soler,

Background

ADPKD has limited therapeutic options. Bempedoic acid (BA), an inhibitor of ATP citrate-lyase (ACLY) FDA-approved for hyperlipidemia, catalyzes a key step in cholesterol synthesis that is important for cell growth and proliferation. BA also activates AMPK in mice. We hypothesized that BA could be a novel ADPKD therapy by inhibiting cyst growth and proliferation and promoting oxidative metabolism via ACLY inhibition and AMPK activation.

Methods

Murine Pkd1-null kidney cell lines derived from either proximal tubule (PT) or collecting duct (IMCD) were grown in Matrigel cultures and treated ± BA before cyst analysis by microscopy. In vivo, male and female Pkd1^fl/fl; Pax8-rtTA; Tet-O-Cre transgenic C57BL/6 mice were induced with IP doxycycline injection on P10&11. Mice were then treated ± BA (30 mg/kg/d) ± tolvaptan (30-100 mg/kg/d) by oral gavage from P12-21. As measures of disease severity, total kidney weight to body weight (TKW/BW) and blood BUN levels at euthanasia (P22) were measured. Kidney homogenates were immunoblotted for expression of key disease biomarkers and other relevant cell signaling markers.

Results

BA dramatically inhibited cystic growth in 3D cultures in PT and IMCD Pkd1-null kidney cells.
In ADPKD mice, BA reduced TKW/BW vs. vehicle at euthanasia (6.9 vs. 11.9%; P<0.01). Similarly, tolvaptan (100 mg/kg/d) reduced TKW/BW to 7.8% vs. vehicle (P<0.05). Addition of BA to tolvaptan caused a further reduction in TKW/BW (4.9%; P<0.05) vs. tolvaptan alone.
BA reduced BUN vs. vehicle (59 vs. 107 mg/dL; P<0.05). Tolvaptan also decreased BUN vs. vehicle at 30 mg/kg/d (68; P<0.05). Again, addition of BA to tolvaptan at 30 mg/kg/d caused a further significant reduction in BUN (38; P<0.05).
BA reduced ACLY and stimulated AMPK activity in kidneys vs. controls. BA also inhibited mTOR and ERK signaling, which are upregulated in ADPKD. BA also sharply reduced kidney injury markers KIM-1 and, to a lesser extent, NGAL. These BA effects occurred alone and in concert with tolvaptan.

Conclusion

BA inhibited cyst growth in vitro and ADPKD severity in vivo. Combined BA and tolvaptan treatment further improved ADPKD outcomes in vivo. BA significantly reduced kidney injury markers and mTOR and ERK signaling. BA may be a promising new ADPKD therapy, having beneficial effects on disease severity when used alone and with tolvaptan in mice.

Funding

• Commercial Support – Esperion Therapeutics, Inc.