Cannabinoid‐1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells

AIMS: To evaluate the specific role of the endocannabinoid/cannabinoid type‐1 (CB(1)R) system in modulating mitochondrial dynamics in the metabolically active renal proximal tubular cells (RPTCs). MATERIALS AND METHODS: We utilized mitochondrially‐targeted GFP in live cells (wild‐type and null for the CB(1)R) and electron microscopy in kidney sections of RPTC‐CB(1)R(‐/‐) mice and their littermate controls. In both in vitro and in vivo conditions, we assessed the ability of CB(1)R agonism or fatty acid flux to modulate mitochondrial architecture and function. RESULTS: Direct stimulation of CB(1)R resulted in mitochondrial fragmentation in RPTCs. This process was mediated, at least in part, by modulating the phosphorylation levels of the canonical fission protein dynamin‐related protein 1 on both S637 and S616 residues. CB(1)R‐induced mitochondrial fission was associated with mitochondrial dysfunction, as documented by reduced oxygen consumption and ATP production, increased reactive oxygen species and cellular lactate levels, as well as a decline in mitochondrial biogenesis. Likewise, we documented that exposure of RPTCs to a fatty acid flux induced CB(1)R‐dependent mitochondrial fission, lipotoxicity and cellular dysfunction. CONCLUSIONS: CB(1)R plays a key role in inducing mitochondrial fragmentation in RPTCs, leading to a decline in the organelle's function and contributing to the renal tubular injury associated with lipotoxicity and other metabolic diseases.