Peripheral CB1R Blockade Suppresses AKI-to-CKD Maladaptive Repair

BackgroundAcute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD), yet mechanisms governing this transition remain poorly understood. The endocannabinoid system (ECS), particularly cannabinoid-1 receptor (CB1R), regulates inflammation and metabolism in various organs, but its role in post-AKI maladaptive repair is less established. MethodsWe analyzed CB1R expression in kidney biopsies from pre- and post-transplant recipients and in murine AKI models (ischemia-reperfusion injury [IRI] and folic acid [FA]-induced AKI). Peripheral CB1R blockade was evaluated in FA-AKI model and in human primary kidney proximal tubule cells (hKPTCs). Spatial metabolomics, semi-targeted metabolomic profiling, and gene and protein expression characterized molecular mechanisms. ResultsCB1R expression was increased in kidneys undergoing maladaptive repair in both humans and mice, but remained unchanged during acute injury. In the FA-induced AKI model, the ECS showed stage-specific alterations, with temporal and spatial fluctuations in endocannabinoid levels and their enzymatic regulators. Peripheral CB1R blockade during the repair phase preserved kidney function, reduced injury, and maintained systemic glucose homeostasis. Metabolomic and molecular analyses revealed that CB1R blockade restored dysregulated arginine metabolism and reduced AKT/NF-{kappa}B-p65 pathway in post-AKI kidneys, linking CB1R activation to inflammatory signaling. In hKPTCs, 2-AG-induced activation of CB1R increased VCAM1 expression, a failed-repair marker, while its antagonism reduced TNF/2-AG-induced expression of pro-inflammatory adhesion molecules, chemokines, cytokines, and arginine metabolism enzymes. ConclusionsCB1R overactivation drives AKI-to-CKD progression by promoting inflammatory signaling and metabolic dysregulation. Peripheral CB1R blockade during the repair phase represents a novel therapeutic strategy to prevent maladaptive repair and CKD development after AKI. These findings establish CB1R as a phase-specific therapeutic target for post-AKI intervention. Translational StatementPeripheral CB1R antagonists offer a first-in-class therapeutic strategy to halt progression from acute kidney injury (AKI) to chronic kidney disease (CKD) by selectively targeting maladaptive tubular repair. By blocking CB1R signaling specifically in the kidney, these agents attenuate inflammation, metabolic dysregulation, and fibrogenic pathways that drive failed repair, while sparing central nervous system CB1R and thereby minimizing neuropsychiatric adverse effects. This phase-specific, peripherally restricted approach supports the development of peripheral CB1R antagonists as a viable translational therapy to improve long-term renal outcomes after AKI.