The complement is a part of the immune system that plays several roles in removing pathogens. Despite the importance of the complement system, the exact role of each component has been overlooked because the complement system was thought to be a nonspecific humoral immune mechanism that worked against pathogens. Decay-accelerating factor (DAF or CD55) is a known inhibitor of the complement system and has recently attracted substantial attention due to its role in various diseases, such as cancer, protein-losing enteropathy, and malaria. Some protein-losing enteropathy cases are caused by CD55 deficiency, which leads to complement hyperactivation, malabsorption, and angiopathic thrombosis. In addition, CD55 has been reported to be an essential host receptor for infection by the malaria parasite. Moreover, CD55 is a ligand of the seven-span transmembrane receptor CD97. Since CD55 is present in various cells, the functional role of CD55 has been expanded by showing that CD55 is associated with a variety of diseases, including cancer, malaria, protein-losing enteropathy, paroxysmal nocturnal hemoglobinuria, and autoimmune diseases. This review summarizes the current understanding of CD55 and the role of CD55 in these diseases. It also provides insight into the development of novel drugs for the diagnosis and treatment of diseases associated with CD55.
The endocannabinoid system (ECS) is activated at the onset of obesity and diverse metabolic diseases. Endocannabinoids mediate their physiological and behavioral effects by activating specific cannabinoid receptors, mainly cannabinoid receptor 1 (CB(1)R). Diabetic nephropathy (DN) is induced by hyperlipidemia, and renal proximal tubule cells are an important site for the onset of DN. However, the pathophysiology of CB(1)R, especially in the hyperlipidemia of DN, has not been elucidated. Therefore, we examined the effect of palmitic acid (PA) on CB(1)R expression and its related signal pathways in human renal proximal tubular cells (HK-2 cells). PA significantly increased CB(1)R mRNA and protein levels and induced CB(1)R internalization. PA-induced activation of CB(1)R is prevented by the treatment of AACOCF(3) (a cPLA(2) inhibitor), indomethacin and NS398 (a COX 2 inhibitors). Indeed, PA increased cPLA(2), and COX-2 but not COX-1. We also investigated whether the PA-induced activation of CB(1)R is linked to apoptosis. As a result, AM251 (a CB(1)R antagonist) attenuated PA-mediated apoptosis in a concentration-dependent manner. Furthermore, PA decreased GRP78 expression and induced increases in the endoplasmic reticulum (ER) stress signaling pathways p-PERK, p-eIF2α, p-ATF4, and CHOP, which were blocked by AM251 treatment. Moreover, PA increased the Bax/Bcl-2 ratio, cleaved PARP, and caspase-3 levels. The PA-induced apoptotic effects were decreased with CB(1)R-specific antagonist (AM251) treatment and CB1 si-RNA transfection. In conclusion, PA induced apoptosis through ER stress via CB(1)R expression in human proximal tubule cells. Our results provide evidence that CB(1)R blockade may be a potential anti-diabetic therapy for the treatment of DN.
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 1R) and cannabinoid receptor 2 (CB2R). However, the pathophysiology of CB 1R in diabetic nephropathy has not been elucidated. We investigated the effects of HG on CB 1R expression and its signaling pathways in primary cultured rat mesangial cells. HG significantly increased CB 1R mRNA and protein levels in a time-dependent manner and induced CB 1R internalization. NF-B and cPLA 2 were involved in the HG-induced increase in CB 1R levels. Using a CB1R antagonist (AM251) and CB1 siRNA transfection, we showed that HG-induced CB 1R 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␣, 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 1R expression by small interfering RNA. We propose a mechanism by which blockade of CB 1R attenuates HG-induced apoptosis in rat mesangial cells. Our findings suggest that blockade of CB 1R may be a potential therapy in diabetic nephropathy. endocannabinoid system DIABETIC NEPHROPATHY IS CHARACTERIZED by hyperglycemia-induced dysfunction of mesangial cells (21). In an environment of high glucose (HG), renal mesangial cells undergo cascades of deleterious reactions, including cell injury and extracellular matrix deposition, which lead to glomeruli dysfunction (1,25,49). Mesangial cell apoptosis promoted by HG contributes to the development of diabetic nephropathy (22,40).Endocannabinoids are endogenous lipid mediators with a wide range of biological effects, similar to those of marijuana. The endocannabinoid system (ECS) regulates synaptic plasticity, emotional responses, energy homeostasis, and glucose metabolism (44). Dysregulation of ECS is involved in the onset of obesity and diabetic nephropathy (12). Barutta et al. (5) have reported that cannabinoid receptor 1 (CB 1 R) was overexpressed within glomeruli in diabetic mice and CB 1 blockade prevented diabetes-induced albuminuria. It has been also reported that the condition of HG increased the endogenous ligands of the ECS, N-arachidonoyl ethanolamine (AEA) and 2-arachidonylglycerol ( 2-AG) in vivo...
The NADPH oxidase, NOX5, is known to stimulate cell proliferation in some cancers by generating reactive oxygen species (ROS). We show here that the long form of NOX5 (NOX5-L) also promotes cell death, and thus determines the balance of proliferation and death, in skin, breast and lung cancer cells. Moderate expression of NOX5-L induced cell proliferation accompanied by AKT and ERK phosphorylation, whereas an increase in NOX5-L above a certain threshold promoted cancer cell death accompanied by caspase-3 activation. Notably, cisplatin treatment increased NOX5-L levels through CREB activation and enhanced NOX5-L activity through augmentation of Ca2+ release and c-Abl expression, ultimately triggering ROS-mediated cancer cell death—a distinct pathway absent in normal cells. These results indicate that NOX5-L determines cellular responses in a concentration- and context-dependent manner.
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