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Kidney Week

Abstract: FR-PO951

Bile Acid Receptor Agonists and Metformin Slow Cyst Growth and Correct Perturbed Energy Metabolism in PKD1-Null Kidney Cells

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Li, Hui, USC Keck School of Medicine, Los Angeles, California, United States
  • Huang, Polly, USC Keck School of Medicine, Los Angeles, California, United States
  • Naser-Tavakolian, Aurash, USC Keck School of Medicine, Los Angeles, California, United States
  • Rivera, Daniel, USC Keck School of Medicine, Los Angeles, California, United States
  • Levi, Moshe, Georgetown University, Washington, District of Columbia, United States
  • Hallows, Kenneth R., USC Keck School of Medicine, Los Angeles, California, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in polycystin-1 (PKD1) or polycystin-2 (PKD2), presents with progressive development of renal cysts and eventual end-stage kidney disease. PKD1-null cells have increased proliferation and decreased AMP-activated kinase (AMPK) activity, along with dysregulated cellular metabolism. Bile acid receptor agonists, INT-777 and INT-767, promote a shift from glycolytic to fatty acid oxidative metabolism and regulate several key signaling pathways, including inflammation, fibrosis and the AMPK and extracellular signal-regulated kinases (ERK) pathways. Here we sought to determine whether these agonists alone or in combination with the AMPK activator metformin, may be effective as novel therapeutics for ADPKD by correcting dysregulated metabolism and slowing cyst growth in PKD1-null cells in vitro.

Methods

Using PKD1-null kidney epithelial cells, we examined AMPK and ERK pathway markers and levels of key glycolytic enzymes by immunoblotting, which were correlated with effects of various treatments. 3-D cultures were used to assess cyst growth after treatment with INT-767 or INT-777 alone or in combination with metformin. Seahorse assays were performed to evaluate cellular metabolic phenotypes under different conditions.

Results

INT-767 treatment of PKD1-null cells activated the AMPK and inhibited the ERK pathways and expression of the key glycolytic enzyme PDK1. INT-767 also reduced glycolytic fluxes while significantly increasing mitochondrial oxidative respiration as compared with control cells. INT-777 treatment also increased fatty acid oxidation in PKD1-null cells. Both INT-767 and INT-777 inhibited cystogenesis of PKD1-null cells in 3D cultures. Moreover, combination INT-767 or INT-777 treatment with metformin, another potential therapeutic for ADPKD, achieved much better control of cyst growth than either drug alone.

Conclusion

The bile acid receptor agonists INT-767 or INT-777 in combination with the AMPK activator metformin appear to have a synergistic effect on slowing cyst growth and correcting perturbed energy metabolism in PKD-deficient ADPKD kidney epithelial cells. These beneficial effects may potentially occur via activation of the AMPK pathway and will be explored further using in vivo ADPKD mouse models.

Funding

  • NIDDK Support