Beneficial Effects of Bempedoic Acid Treatment in Polycystic Kidney Disease Cells and Mice

Abstract

Background: ADPKD has few therapeutic options. Tolvaptan slows disease but has side effects limiting its tolerability. Bempedoic acid (BA), an ATP citrate-lyase (ACLY) inhibitor FDA-approved for hypercholesterolemia, catalyzes a key step in fatty acid/sterol synthesis 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, proliferation, injury, and metabolic dysregulation via ACLY inhibition and AMPK activation. Methods: ACLY gene and protein expression levels were measured in murine Pkd1-null kidney cell lines derived from proximal tubule (PT) and collecting duct (IMCD), grown in 3D Matrigel cultures and treated +/- BA before cyst analysis. Mitochondria were also characterized using MitoSox and MitoTracker staining. Pkd1fl/fl;Pax8-rtTA;Tet-O-Cre C57BL/6J mice were induced with IP doxycycline injection on postnatal days 10 and 11 (P10 and P11) and then treated +/- BA (30 mg/kg/d) +/- tolvaptan (30-100 mg/kg/d) by oral gavage from P12-21. To assess disease severity, %total kidney weight-to-body weight (%TKW/BW) and BUN levels at euthanasia (P22) were measured. Kidney and liver homogenates were immunoblotted for expression of key disease and other cellular signaling biomarkers. Results: ACLY protein expression and activity were upregulated in ADPKD kidney tissues relative to wild-type. BA inhibited cystic growth in both PT and IMCD-derived Pkd1-null kidney cells. BA also inhibited mitochondrial superoxide production and promoted mitochondrial elongation in these cells, suggesting improved mitochondrial function. In ADPKD mice, BA reduced %TKW/BW and BUN to a similar extent as tolvaptan relative to untreated controls. Addition of BA to tolvaptan caused a further reduction in %TKW/BW and BUN vs. tolvaptan alone. BA reduced ACLY and stimulated AMPK activity in kidneys vs. controls. BA also inhibited mTOR and ERK signaling and sharply reduced the injury marker KIM-1 and, to a lesser extent, NGAL. In liver, BA increased mitochondrial biogenesis while inhibiting apoptosis. These BA effects occurred alone and together with tolvaptan. Conclusion: BA inhibited cyst growth in vitro and ADPKD severity in vivo. Combining BA with tolvaptan further improved various ADPKD disease parameters. Repurposing BA may be a promising new ADPKD therapeutic strategy, having beneficial effects when used alone and along with tolvaptan in mice.