RESUMEN
Although chronic kidney disease (CKD) is strongly associated with onsets of cardiovascular disease (CVD), the pathogenic mechanism between these diseases has not been fully understood. To develop and validate new therapeutic strategies for this complication, appropriate experimental models that reflect the complexity of the underlying pathophysiology are needed. The Osborne-Mendel (OM) rat was identified as an atherosclerosis-prone and a premature-death rat strain among 16 inbred rat strains when fed high-cholesterol containing diet. When fed high-cholesterol diet, OM rats showed simultaneous occurrence of aortic aneurysm, aortic dissection, peripheral artery occlusion, and left atrial thrombosis. OM rats had significantly lower max dP/dt and higher min dP/dt than F344 rats did, indicating impaired left ventricle contractility and relaxation. OM rats developed renal dysfunction, showing increased urinary albumin excretion. OM rats also showed mild hypertension, decreased endothelial function, and enhanced coagulation and platelet aggregation, compared with F344 rats. We now report that OM rat would be a novel spontaneous animal model which simultaneously demonstrates cardiac and renal dysfunction, and CVD events. This model could be a useful model for the pre-clinical testing of pharmacological therapies and could provide new insight into potential targets and pathways for the treatment of CKD and CVD.
Asunto(s)
Aneurisma de la Aorta/fisiopatología , Arteriopatías Oclusivas/fisiopatología , Cardiopatías/fisiopatología , Enfermedades Renales/fisiopatología , Enfermedad Arterial Periférica/fisiopatología , Trombosis/fisiopatología , Animales , Aneurisma de la Aorta/etiología , Arteriopatías Oclusivas/etiología , Presión Sanguínea/efectos de los fármacos , Colesterol en la Dieta/administración & dosificación , Colesterol en la Dieta/toxicidad , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Atrios Cardíacos , Cardiopatías/etiología , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Enfermedades Renales/etiología , Masculino , Enfermedad Arterial Periférica/etiología , Ratas Endogámicas F344 , Ratas Endogámicas , Especificidad de la Especie , Análisis de Supervivencia , Trombosis/etiología , Factores de TiempoRESUMEN
AIM: Low-density lipoprotein receptor knockout (LDLR-KO) mice fed a modified choline-deficient and amino acid-defined (mCDAA) diet show non-alcoholic steatohepatitis (NASH)-like pathophysiology. In order to pharmacologically benchmark this model, effects of pioglitazone (a thiazolidinedione) and candesartan cilexetil (an angiotensin II type 1 receptor blocker) on steatosis and liver fibrosis were examined. METHODS: Pioglitazone (10 mg/kg) and candesartan cilexetil (3 mg/kg) were given orally once daily to LDLR-KO mice under mCDAA diet for 7 weeks. Blood biochemistry and hepatic histology were assessed, and hepatic gene expression levels and triglyceride content were measured. RESULTS: Pioglitazone suppressed hepatic COL1A1 gene expression by 43% and attenuated hepatic fibrosis areas by 49%. Pioglitazone also decreased plasma alanine aminotransferase levels, liver weight, hepatic triglyceride content, and hepatic expression of other fibrosis-related genes such as TGFB1, SPP1, TIMP1, and IL6. Candesartan cilexetil suppressed hepatic COL1A1 gene expression by 33%, whereas the other end-points including hepatic fibrosis areas were not affected. CONCLUSIONS: Pioglitazone showed anti-fibrotic effects accompanied by improving hepatic transaminase activity and hepatic lipid accumulation, but the effect of candesartan cilexetil was only limited, unlike previous reports for angiotensin II type 1 receptor blockers. As the pharmacological effects of pioglitazone in the current animal model are similar to those reported in patients with NASH, this model may represent some aspects of the pathophysiology of NASH. Further profiling using other agents or mechanisms that have been tested in the clinic will better clarify the utility of the animal model.
RESUMEN
Inositol hexakisphosphate kinase 3 (IP6K3) generates inositol pyrophosphates, which regulate diverse cellular functions. However, little is known about its own physiological role. Here, we show the roles of IP6K3 in metabolic regulation. We detected high levels of both mouse and human IP6K3 mRNA in myotubes and muscle tissues. In human myotubes, IP6K3 was upregulated by dexamethasone treatment, which is known to inhibit glucose metabolism. Furthermore, Ip6k3 expression was elevated under diabetic, fasting, and disuse conditions in mouse skeletal muscles. Ip6k3(-/-) mice demonstrated lower blood glucose, reduced circulating insulin, deceased fat mass, lower body weight, increased plasma lactate, enhanced glucose tolerance, lower glucose during an insulin tolerance test, and reduced muscle Pdk4 expression under normal diet conditions. Notably, Ip6k3 deletion extended animal lifespan with concomitant reduced phosphorylation of S6 ribosomal protein in the heart. In contrast, Ip6k3(-/-) mice showed unchanged skeletal muscle mass and no resistance to the effects of high fat diet. The current observations suggest novel roles of IP6K3 in cellular regulation, which impact metabolic control and lifespan.
Asunto(s)
Metabolismo Energético/fisiología , Longevidad/fisiología , Fosfotransferasas (Aceptor del Grupo Fosfato)/fisiología , Animales , Composición Corporal , Peso Corporal , Línea Celular , Dexametasona/farmacología , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético/genética , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Islotes Pancreáticos/enzimología , Longevidad/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Fibras Musculares Esqueléticas/enzimología , Músculo Esquelético/enzimología , Miocardio/metabolismo , Especificidad de Órganos , Fosforilación , Fosfotransferasas (Aceptor del Grupo Fosfato)/deficiencia , Fosfotransferasas (Aceptor del Grupo Fosfato)/genética , Procesamiento Proteico-Postraduccional , Ratas , Proteína S6 Ribosómica/metabolismoRESUMEN
Relaxin-3 is a neuropeptide belonging to the relaxin/insulin superfamily. Studies using rodents have revealed that relaxin-3 is predominantly expressed in neurons in the nucleus incertus (NI) of the pons, the axons of which project to forebrain regions including the hypothalamus. There is evidence that relaxin-3 is involved in several functions, including food intake and stress responses. In the present study, we generated relaxin-3 gene knockout (KO) mice and examined them using a range of behavioral tests of sensory/motor functions and emotion-related behaviors. The results revealed that relaxin-3 KO mice exhibited normal growth and appearance, and were generally indistinguishable from wild genotype littermates. There was no difference in bodyweight among genotypes until at least 28 weeks after birth. In addition, there were no significant differences between wild-type and KO mice in locomotor activity, social interaction, hot plate test performance, fear conditioning, depression-like behavior, and Y-maze test performance. However, in the elevated plus maze test, KO mice exhibited a robust increase in the tendency to enter open arms, although they exhibited normal performance in a light/dark transition test and showed no difference from wild-type mice in the time spent in central area in the open field test. On the other hand, a significant increase in the acoustic startle response was observed in KO mice. These results indicate that relaxin-3 is slightly involved in the anxiety-related behavior.
RESUMEN
BACKGROUND: Apelin is an endogenous ligand for the G-protein-coupled 7-transmembrane receptor, APJ. The administration of apelin-13, a truncated 13-amino acid apelin peptide, in diet-induced obese mice is reported to result in a decrease in adiposity due to the increase of energy expenditure with an increase in the expression of uncoupling proteins. METHODS: We systematically compared the phenotype of human apelin-transgenic (apelin-Tg) mice fed standard or high-fat diets (HFD) with that of non-Tg control mice to clarify the effect of apelin on obesity. The beneficial effects of apelin were evaluated by multiple assay methods including indirect calorimetrical measurements, gene expression analysis, and immunohistochemical staining. RESULTS: Apelin-Tg mice inhibited HFD-induced obesity without altering food intake and exhibited increased oxygen consumption and body temperature compared to non-Tg controls. Interestingly, the mRNA expressions of angiopoietin-1 (Ang1), a key molecule for vascular maturation, and its receptor, endothelium-specific receptor tyrosine kinase 2 (Tie2), were significantly upregulated in the skeletal muscle of HFD-fed apelin-Tg mice, and the areas of anti-CD31 antibody-positive endothelial cells also increased. Furthermore, both the aerobic type-I muscle fibre ratio and the DNA copy number of mitochondrial NADH dehydrogenase subunit 1 increased 2.0- and 1.4-fold in skeletal muscle, respectively. CONCLUSIONS: These findings suggest that apelin stimulates energy expenditure via increase vascular mass and mitochondrial biogenesis in skeletal muscle. GENERAL SIGNIFICANCE: Apelin is a prerequisite factor for anti-obesity by stimulating energy expenditure via regulating homeostatic energy balance.
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Grasas de la Dieta/efectos adversos , Péptidos y Proteínas de Señalización Intercelular/genética , Mitocondrias Musculares/genética , Obesidad/fisiopatología , Tejido Adiposo/crecimiento & desarrollo , Angiopoyetina 1/biosíntesis , Animales , Apelina , Temperatura Corporal/fisiología , Humanos , Masculino , Ratones , Ratones Transgénicos , Músculo Esquelético/fisiología , Obesidad/metabolismo , Consumo de Oxígeno , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Receptor TIE-2RESUMEN
OBJECTIVE: GPR40 is a G protein-coupled receptor regulating free fatty acid-induced insulin secretion. We generated transgenic mice overexpressing the hGPR40 gene under control of the mouse insulin II promoter and used them to examine the role of GPR40 in the regulation of insulin secretion and glucose homeostasis. RESEARCH DESIGN AND METHODS: Normal (C57BL/6J) and diabetic (KK) mice overexpressing the hGPR40 gene under control of the insulin II promoter were generated, and their glucose metabolism and islet function were analyzed. RESULTS: In comparison with nontransgenic littermates, hGPR40 transgenic mice exhibited improved oral glucose tolerance with an increase in insulin secretion. Although islet morphologic analysis showed no obvious differences between hGPR40 transgenic and nontransgenic mice, isolated islets from hGPR40 transgenic mice had enhanced insulin secretion in response to high glucose (16 mmol/l) compared with those from nontransgenic mice, and they both had similar low glucose (3 mmol/l)-stimulated insulin secretion. In addition, hGPR40 transgenic islets significantly increased insulin secretion against a naturally occurring agonist palmitate in the presence of 11 mmol/l glucose. hGPR40 transgenic mice were also found to be resistant to high-fat diet-induced glucose intolerance, and hGPR40 transgenic mice harboring KK background showed augmented insulin secretion and improved oral glucose tolerance compared with nontransgenic littermates. CONCLUSIONS: Our results suggest that GPR40 may have a role in regulating glucose-stimulated insulin secretion and plasma glucose levels in vivo and that pharmacological activation of GPR40 may provide a novel insulin secretagogue beneficial for the treatment of type 2 diabetes.
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Glucemia/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Glucosa/farmacología , Células Secretoras de Insulina/fisiología , Insulina/metabolismo , Receptores Acoplados a Proteínas G/genética , Animales , Cartilla de ADN , Ácidos Grasos no Esterificados/metabolismo , Regulación de la Expresión Génica , Insulina/genética , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regiones Promotoras Genéticas , ARN/genética , ARN/aislamiento & purificación , Receptores Acoplados a Proteínas G/fisiología , Valores de ReferenciaRESUMEN
The human MrgX3 gene, belonging to the mrgs/SNSRs (mas related genes/sensory neuron specific receptors) family, was overexpressed in transgenic rats using the actin promoter. Two animal lines showed cataracts with liquification/degeneration and swelling of the lens fiber cells. The transient epidermal desquamation was observed in line with higher gene expression. Histopathology of the transgenic rats showed acanthosis and focal parakeratosis. In the epidermis, there was an increase in cellular keratin 14, keratin 10, and loricrin, as well as PGP 9.5 in innervating nerve fibers. These phenotypes accompanied an increase in the number of proliferating cells. These results suggest that overexpression of the human MrgX3 gene causes a disturbance of the normal cell-differentiation process.
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Catarata/genética , Catarata/patología , Receptores Acoplados a Proteínas G/metabolismo , Anomalías Cutáneas/genética , Anomalías Cutáneas/metabolismo , Animales , Animales Modificados Genéticamente , Catarata/metabolismo , Diferenciación Celular , Expresión Génica/genética , Humanos , Fenotipo , Ratas , Receptores Acoplados a Proteínas G/genética , Anomalías Cutáneas/patologíaRESUMEN
Human LCAT-like lysophospholipase (LLPL), or lysophospholipase 3, was first identified in vitro, in foam cells derived from THP-1 cells. We demonstrated that LLPL was present in foam cells in the severe atherosclerotic lesions that develop in apolipoprotein E-null (apoE(-/-)) mice. This indicated that LLPL might affect lipid metabolisms in foam cells and, therefore, atherogenesis. Accordingly, we created LLPL-knockout mice by gene targeting and crossed them with apoE(-/-) mice. We showed that the absence of LLPL increased lesion formation markedly in apoE(-/-) mice but had little effect on the plasma-lipid profile. In addition, LLPL-deficient peritoneal macrophages were more sensitive to apoptosis induced by exposure to oxidized low-density lipoprotein. LLPL might provide a link between apoptosis in macrophages and atherogenesis. Our data demonstrate that LLPL activity is anti-atherogenic and indicate that the regulation of this enzyme might be a novel drug target for the treatment of atherosclerosis.