Progressive endocannabinoid system dysregulation in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, inflammation, and metabolic dysregulation. The endocannabinoid system (ECS), particularly the cannabinoid-1 receptor (CB1R), regulates renal metabolism and inflammatory signaling, yet its role in ADPKD remains largely unexplored. We analyzed publicly available human kidney transcriptomic datasets (bulk microarray GSE7869; single-nucleus RNA-sequencing from ADPKD GSE185948, and diabetic kidney disease cohorts GSE195460) and validated findings in ADPKD patient kidney tissue versus non-cystic controls using quantitative PCR, liquid chromatography-tandem mass spectrometry, and Western blotting. Longitudinal disease progression was evaluated in Pkd1RC/RC mice at 3, 6, 9, and 12 months, with comprehensive assessment of ECS components, endocannabinoid (eCB) levels, and kidney function parameters. Correlation examined associations between ECS markers and disease severity. Human ADPKD kidneys demonstrated consistent upregulation of CNR1 transcripts across platforms, with single-nucleus analysis revealing enrichment in proximal tubule-derived populations including failed-repair proximal tubule cells. ADPKD tissue exhibited significant reductions in key ECS-metabolizing enzymes (FAAH, NAPEPLD, MGLL) and marked depletion of eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG). In contrast, diabetic kidney disease showed minimal ECS alterations, indicating ADPKD-specific dysregulation. Pkd1RC/RC mice recapitulated human findings, with Cnr1 upregulation beginning at 6 months and significant AEA/N-oleoylethanolamine (OEA) depletion at 9–12 months. CB1R protein elevation preceded ligand depletion, suggesting progressive receptor sensitization. Correlation analyses revealed robust associations between CB1R/enzyme expression, eCB depletion, and declining kidney function (kidney weight-to-body weight ratio, blood urea nitrogen, and creatinine clearance). ADPKD kidneys exhibit disease-specific dysregulation of the ECS, characterized by increased CB1R expression accompanied by paradoxical depletion of eCB ligands. These alterations correlate with cyst burden and functional decline across human and murine disease stages, identifying the ECS as a prominently affected pathway during ADPKD progression. While our findings establish a strong association between ECS dysregulation and disease severity, whether altered CB1R signaling represents a causal driver of cystogenesis or a secondary, yet therapeutically targetable component of the cystic and injury response will require direct genetic or pharmacologic modulation of CB1R/ECS signaling.