Cannabidiol attenuates kidney injury and mitochondrial calcium dysregulation in experimental cardiorenal syndrome

Abstract Cardiorenal syndrome (CRS) is characterized by bidirectional heart–kidney dysfunction in which oxidative stress, inflammation, and mitochondrial dysfunction drive progressive kidney injury, but the role of mitochondrial calcium (Ca²⁺) handling through the mitochondrial calcium uniporter (MCU) complex remains unclear. Here we show, in a mouse model of CRS induced by angiotensin II and L-NAME in male mice (C57BL/6), that renal mitochondria exhibit increased MCU expression, reduced Ca²⁺ retention capacity, and greater susceptibility to Ca²⁺-induced permeability transition, alongside impaired respiration, reduced PGC-1α and TFAM expression, oxidative stress, and inflammatory activation. Cannabidiol (CBD) attenuates renal dysfunction and structural injury, restores mitochondrial respiratory capacity and complex I activity, normalizes MCU expression, and partially improves mitochondrial Ca²⁺ handling, independently of blood pressure reduction. These findings identify MCU-dependent mitochondrial Ca²⁺ dysregulation as a candidate mechanism linking mitochondrial dysfunction to renal injury in CRS, and a potential target for CBD’s nephroprotective effects.