Activation of Apelin Receptor Inhibits Cystogenesis in a Mouse Model of Polycystic Kidney Disease

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder characterized by increased cAMP signaling, cell proliferation, and fluid accumulation within the cysts. Tolvaptan is approved for ADPKD treatment, but its use is limited by various adverse effects, leaving an unmet clinical need for safe and effective therapy. The apelin receptor is a Gαi-coupled receptor which binds two endogenous ligands, apelin and Elabela/Toddler, to promote vasodilation, hypotension, and a decrease in cardiac hypertrophy. ADPKD patients have reduced circulating apelin which is associated with tubular damage, disease progression, and poor survival. We hypothesized that low apelin signaling in ADPKD contributes to cystogenesis and that exogenous apelin may ameliorate disease. Methods: Male and female Pkd1RC/RC; Pkd2+/− (PKD) mice were given 2 mg/kg body weight (BW) [Pyr1]apelin-13, the small molecule apelin receptor agonist azelaprag (2 mg/kg), the vasopressin receptor antagonist mozavaptan (0.1% in food), or vehicle control by daily intraperitoneal injection for 27 days. Tail-cuff plethysmography was obtained, animals were euthanized, and the kidneys and heart were harvested. Kidney weight (%KW/BW) and heart weight (HW/BW), a measure of hypertrophy, were assessed. Blood urea nitrogen, an indicator of renal function, was determined by ELISA. Human ADPKD cells were cultured to form in vitro cysts in a 3D collagen matrix and treated with apelin receptor agonists for 7 days, and then cyst number and cystic area were analyzed. Results: Exogenous [Pyr1]apelin-13 significantly reduced %KW/BW (2.36±0.14 vs 1.70±0.04, p<0.0001) similar to mozavaptan (2.36±0.14 vs 1.75±0.06, p<0.0001), when compared to vehicle. Azelaprag, had a mild but significant reduction on %KW/BW (2.36±0.14 vs 1.93±0.06, p<0.01). Both [Pyr1]apelin-13 and mozavaptan significantly reduced BUN in these animals. Cystic animals did not show any evidence for cardiac hypertrophy (HW/BW) and their blood pressure remained unaffected. Preliminary data from APDKD cells grown in 3D cell culture suggest inhibition of cyst formation by both apelin and azelaprag. Conclusion: Targeting apelin receptor signaling may be a novel therapeutic strategy for treating ADPKD. Future experiments will explore the molecular mechanisms mediating the effects of apelin on cystogenesis. Funding: Private Foundation Support