RESUMEN
Vascular calcification decreases compliance and increases morbidity. Mechanisms of this process are unclear. The role of oxidative stress and effects of antioxidants have been poorly explored. We investigated effects of the antioxidants lipoic acid (LA) and tempol in a model of atherosclerosis associated with elastocalcinosis. Male New Zealand white rabbits (2.5-3.0 kg) were fed regular chow (controls) or a 0.5% cholesterol (chol) diet+104 IU/day vitamin D2 (vitD) for 12 weeks, and assigned to treatment with water (vehicle, n=20), 0.12 mmol·kg-1·day-1 LA (n=11) or 0.1 mmol·kg-1·day-1 tempol (n=15). Chol+vitD-fed rabbits developed atherosclerotic plaques associated with expansive remodeling, elastic fiber disruption, medial calcification, and increased aortic stiffness. Histologically, LA prevented medial calcification by â¼60% and aortic stiffening by â¼60%. LA also preserved responsiveness to constrictor agents, while intima-media thickening was increased. In contrast to LA, tempol was associated with increased plaque collagen content, medial calcification and aortic stiffness, and produced differential changes in vasoactive responses in the chol+vitD group. Both LA and tempol prevented superoxide signals with chol+vitD. However, only LA prevented hydrogen peroxide-related signals with chol+vitD, while tempol enhanced them. These data suggest that LA, opposite to tempol, can minimize calcification and compliance loss in elastocalcionosis by inhibition of hydrogen peroxide generation.
Asunto(s)
Arteriosclerosis/prevención & control , Óxidos N-Cíclicos/administración & dosificación , Ácido Tióctico/administración & dosificación , Calcificación Vascular/prevención & control , Animales , Aorta Torácica , Arteriosclerosis/inducido químicamente , Arteriosclerosis/metabolismo , Adaptabilidad/efectos de los fármacos , Adaptabilidad/fisiología , Modelos Animales de Enfermedad , Masculino , Conejos , Marcadores de Spin , Calcificación Vascular/inducido químicamente , Resistencia Vascular , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
Vascular calcification decreases compliance and increases morbidity. Mechanisms of this process are unclear. The role of oxidative stress and effects of antioxidants have been poorly explored. We investigated effects of the antioxidants lipoic acid (LA) and tempol in a model of atherosclerosis associated with elastocalcinosis. Male New Zealand white rabbits (2.5-3.0 kg) were fed regular chow (controls) or a 0.5% cholesterol (chol) diet+104 IU/day vitamin D2 (vitD) for 12 weeks, and assigned to treatment with water (vehicle, n=20), 0.12 mmol·kg-1·day-1 LA (n=11) or 0.1 mmol·kg-1·day-1 tempol (n=15). Chol+vitD-fed rabbits developed atherosclerotic plaques associated with expansive remodeling, elastic fiber disruption, medial calcification, and increased aortic stiffness. Histologically, LA prevented medial calcification by ∼60% and aortic stiffening by ∼60%. LA also preserved responsiveness to constrictor agents, while intima-media thickening was increased. In contrast to LA, tempol was associated with increased plaque collagen content, medial calcification and aortic stiffness, and produced differential changes in vasoactive responses in the chol+vitD group. Both LA and tempol prevented superoxide signals with chol+vitD. However, only LA prevented hydrogen peroxide-related signals with chol+vitD, while tempol enhanced them. These data suggest that LA, opposite to tempol, can minimize calcification and compliance loss in elastocalcionosis by inhibition of hydrogen peroxide generation.
Asunto(s)
Animales , Masculino , Conejos , Arteriosclerosis/prevención & control , Óxidos N-Cíclicos/administración & dosificación , Ácido Tióctico/administración & dosificación , Calcificación Vascular/prevención & control , Aorta Torácica , Arteriosclerosis/inducido químicamente , Arteriosclerosis/metabolismo , Adaptabilidad/efectos de los fármacos , Adaptabilidad/fisiología , Modelos Animales de Enfermedad , Marcadores de Spin , Resistencia Vascular , Calcificación Vascular/inducido químicamente , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
Leptin, an adipose-secreted hormone, links metabolism and immunity. Our aim was to determine whether leptin affects the alloimmune response. We used an allogeneic skin transplant model as a means to analyze the allograft immune response in Lep(ob/ob) and wild-type mice. Leptin deficiency results in an increased frequency of Treg and Th2 cells and a prolonged graft survival. These effects of leptin deficiency indicate the importance of leptin and obesity in modulating the allograft immune responses. Our data suggest a possible explanation for the increased susceptibility of hyperleptinemic obese patients to acute and chronic graft rejection.
Asunto(s)
Supervivencia de Injerto/fisiología , Leptina/fisiología , Células Th2/inmunología , Animales , Citometría de Flujo , Prueba de Cultivo Mixto de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , Trasplante HomólogoRESUMEN
Food intake and nutritional status modify the physiological responses of the immune system to illness and infection and regulate the development of chronic inflammatory processes, such as kidney disease. Adipose tissue secretes immune-related proteins called adipokines that have pleiotropic effects on both the immune and neuroendocrine systems, linking metabolism and immune physiology. Leptin, an adipose tissue-derived adipokine, displays a variety of immune and physiological functions, and participates in several immune responses. Here, we review the current literature on the role of leptin in kidney diseases, linking adipose tissue and the immune system with kidney-related disorders. The modulation of this adipose hormone may have a major impact on the treatment of several immune- and metabolic-related kidney diseases.
Asunto(s)
Tejido Adiposo/metabolismo , Enfermedades Renales/etiología , Leptina/fisiología , Adiponectina/biosíntesis , Adiponectina/fisiología , Autoinmunidad , Metabolismo Energético/fisiología , Humanos , Enfermedades Renales/inmunología , Leptina/biosíntesis , Leptina/inmunología , Fenómenos Fisiológicos de la Nutrición , Obesidad/inmunología , Obesidad/fisiopatologíaRESUMEN
Bone morphogenetic protein-7 (BMP-7) is a secreted multifunctional growth factor of the TGF-beta superfamily, which is predominantly known for its osteoinductive properties and emerging potential for treatment of kidney diseases. The mature 34-38 kDa disulfide-linked homodimer protein plays a key role in the differentiation of mesenchymal cells into bone and cartilage. In this study, the full-length sequence of hBMP-7 was amplified and, then, cloned, expressed, and purified from the conditioned medium of 293T cells stably transfected with a lentiviral vector. The mature protein dimer form was properly secreted and recognized by anti-BMP-7 antibodies, and the protein was shown to be glycosilated by treatment with exoglycosidase, followed by western blotting. Moreover, the activity of the purified protein was demonstrated both in vitro, by alkaline phosphatase activity in C2C12 cells, and in vivo by induction of ectopic bone formation in Balb/c Nude mice after 21 days, respectively. This recombinant protein platform may be very useful for expression of different human cytokines and other proteins for medical applications.