Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells

Lim JC, Lim SK, Park MJ, Kim GY, Han HJ, Park SH. Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells. Am J Physiol Renal Physiol 301: F179-F188, 2011. First published February 16, 2011; doi: 10.1152/ajprenal.00032.2010.-The endocannabinoid system in animals and humans is involved in the onset of diverse diseases, including obesity and diabetic nephropathy, which is a major end-stage renal disease characterized by high glucose (HG)induced apoptosis of mesangial cells. Endocannabinoids induce physiological and behavioral effects by activating two specific receptors, cannabinoid receptor 1 (CB(1)R) and cannabinoid receptor 2 (CB(2)R). However, the pathophysiology of CB(1)R in diabetic nephropathy has not been elucidated. We investigated the effects of HG on CB1R expression and its signaling pathways in primary cultured rat mesangial cells. HG significantly increased CB(1)R mRNA and protein levels in a time-dependent manner and induced CB(1)R internalization. NF-kappa B and cPLA(2) were involved in the HG-induced increase in CB1R levels. Using a CB(1)R antagonist (AM251) and CB(1) siRNA transfection, we showed that HG-induced CB(1)R is linked to apoptosis. Specifically, HG inhibited the expression of GRP78, but induced increases in endoplasmic reticulum (ER) stress proteins, including phosphorylated (p)-protein kinase-like ER-associated kinase, p-eukaryotic initiation factor 2 alpha, p-activating transcription factor-4, and C/EBP homologous protein. In addition, HG increased the Bax/Bcl-2 ratio and increased the amounts of cleaved poly(ADP-ribose) polymerase and caspase-3. These apoptotic effects were prevented by AM251 and by the downregulation of CB(1)R expression by small interfering RNA. We propose a mechanism by which blockade of CB(1)R attenuates HG-induced apoptosis in rat mesangial cells. Our findings suggest that blockade of CB(1)R may be a potential therapy in diabetic nephropathy.