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Kidney Week

Abstract: FR-PO720

β3-Adrenergic Receptor: Possible New Drug Targets for the Treatment of Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Schena, Giorgia, Yale University School of Medicine, New Haven, Connecticut, United States
  • Gerbino, Andrea, University of Bari "Aldo Moro", Bari, Italy
  • Carmosino, Monica, University of Basilicata, Italy, Potenza, Italy
  • Caplan, Michael J., Yale University School of Medicine, New Haven, Connecticut, United States
Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic condition caused by mutations in either Polycystin 1 or Polycystin 2 genes and characterized by the formation of fluid filled cysts in the renal parenchyma. Elevations of intracellular cAMP are a major driver of cyst growth. Inhibition of cAMP accumulation in vasopressin-sensitive nephron segments currently constitutes the only approved therapy for ADPKD. Interestingly, sympathetic nerve activity is elevated in patients with chronic kidney disease and this over-activity has been implicated in cystogenesis. Since β3-adrenoreceptors (β3-ARs) are expressed in multiple nephron segments we wished to characterize their signaling pathway in ADPKD and their potential role in its pathogenesis.

Methods

Murine cell lines heterozygous (Pkd1+/-) or homozygous (Pkd1-/-) for a deletion in Pkd1 gene were stably transfected with β3-AR, then seeded in 3D matrix and stimulated with Mirabegron, a selective β3-AR agonist. Cyst size and number were measured using ImageJ. cAMP levels in treated cells were measured via Fluorescence Resonance Energy Transfer (FRET). β3-AR expression was studied via WB on total kidney lysates from an ADPKD mouse model (Pkd1fl/fl; Pax8rtTA; TetO-Cre). Mice were treated with either β3-AR antagonist SR59230A (4mg/kg/day) for 4 weeks or saline. Finally animals were sacrificed and kidney parameters measured.

Results

We found that, upon treatment with Mirabegron, Pkd1-/-3-AR cells form larger and more numerous cysts than untransfected Pkd1-/- cells. FRET analysis confirmed that this effect is associated with a significant increase in cAMP levels elicited by β3-AR activation. Using our ADPKD mouse model we found that renal β3-AR expression is up-regulated in cystic animals versus healty littermates. Most importantly, treatment of these mice with SR59230A leads to improved kidney/body weight ratios and Blood Urea Nitrogen levels in the treated animals versus controls.

Conclusion

Our in vitro data indicate that modulating the activity of β3-AR has a direct effect on cystogenesis. Our in vivo data further suggest that β3-ARs are potentially interesting therapeutic targets in the treatment of ADPKD in that antagonizing β3-AR activity may reduce cAMP accumulation and thus cyst growth in both vasopressin-sensitive and insensitive nephron segments.

Funding

  • NIDDK Support