Exploring Therapeutic Potential of Neuropeptide Y in an ADPKD Mouse Model

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of monogenic cystic kidney disease that often leads to End Stage Renal Disease (ESRD). Addressing the aberrant cAMP-PKA signaling pathway within cyst-lining renal epithelial cells has emerged as a promising therapeutic avenue for ADPKD patients. This study endeavors to delve into the influence of Neuropeptide Y (NPY) and its kidney-specific Gi-coupled receptors on modulating cAMP-PKA signaling and consequent ADPKD progression in the Pkd1RC/RCmouse model. Methods: Pkd1RC/RC mice, aged 3 weeks and exhibiting similar Total Kidney Volume (TKV), were chosen and allocated randomly into control, Low dose NPY, and High dose NPY groups (n = 10/gender/group). Subsequently, these Pkd1RC/RCmice received intraperitoneal injections of 0.1mg/kg or 0.3mg/kg NPY for a further 12 weeks. Following the study period, magnetic resonance imaging (MRI) was conducted to ascertain Total Kidney Volume (TKV), while kidney samples were harvested for cystic index and cystic volume analysis. Plasma samples were also collected for Blood Urea Nitrogen (BUN) assessment. Statistical analysis was carried out utilizing two-way ANOVA. Results: A significant reduction in TKV was observed in NPY-treated groups in comparison to the control group. Furthermore, although statistical significance was not attained, a dose-dependent downward trend in cystic index and cystic volume was noted. We observed a statistically significant decrease of BUN levels in low dose NPY group (22.2 ± 4.5 mg/dL) as compared to control (26.4 ± 6.0 mg/dL), while BUN in high dose treatment group also showed a trend of decrease (23.4 ± 5.7 mg/dL). Conclusion: Our current study underscores the therapeutic potential of NPY in decelerating ADPKD progression within a preclinical mouse model. Future directions will entail 1) optimizing and augmenting NPY dosage for ADPKD mice treatment, 2) delineating and functionally distinguishing kidney-expressed NPY receptors in human and mouse renal epithelial cells, and 3) investigating the molecular interplay between NPY and Polycystin signaling in the context of ADPKD. Funding: Other U.S. Government Support