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1.
Mol Ther ; 25(1): 165-180, 2017 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-28129112

RESUMEN

Diabetic nephropathy is the main cause of end-stage renal disease. MicroRNAs are powerful regulators of the genome, and global expression profiling revealed miR-21 to be among the most highly regulated microRNAs in kidneys of mice with diabetic nephropathy. In kidney biopsies of diabetic patients, miR-21 correlated with tubulointerstitial injury. In situ PCR analysis showed a specific enrichment of miR-21 in glomerular cells. We identified cell division cycle 25a (Cdc25a) and cyclin-dependent kinase 6 (Cdk6) as novel miR-21 targets in mesangial cells. miR-21-mediated repression of Cdc25a and Cdk6 resulted in impaired cell cycle progression and subsequent mesangial cell hypertrophy. miR-21 increased podocyte motility by regulating phosphatase and tensin homolog (Pten). miR-21 antagonism in vitro and in vivo in streptozotocin-induced diabetic mice decreased mesangial expansion, interstitial fibrosis, macrophage infiltration, podocyte loss, albuminuria, and fibrotic- and inflammatory gene expression. In conclusion, miR-21 antagonism rescued various functional and structural parameters in mice with diabetic nephropathy and, thus, might be a viable option in the treatment of patients with diabetic kidney disease.


Asunto(s)
Nefropatías Diabéticas/genética , Silenciador del Gen , MicroARNs/genética , Animales , Puntos de Control del Ciclo Celular/genética , Movimiento Celular , Análisis por Conglomerados , Quinasa 6 Dependiente de la Ciclina/genética , Diabetes Mellitus Experimental , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/terapia , Modelos Animales de Enfermedad , Fibrosis , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Células Mesangiales/metabolismo , Ratones , Podocitos/metabolismo , Interferencia de ARN , Fosfatasas cdc25/genética
2.
Am J Physiol Heart Circ Physiol ; 311(4): H927-H943, 2016 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-27521417

RESUMEN

Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4 High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria.


Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Hipertrofia Ventricular Izquierda/metabolismo , Mitocondrias Cardíacas/metabolismo , Estrés Oxidativo , Estado Prediabético/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Adipoquinas/metabolismo , Tejido Adiposo , Animales , Apoptosis , Autofagia , Composición Corporal , Proteínas de Unión al Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas , Diástole , Dieta Alta en Grasa , Ecocardiografía , GTP Fosfohidrolasas , Proteínas de Choque Térmico/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Proteínas de la Membrana/metabolismo , Microscopía Electrónica , Mitocondrias Cardíacas/ultraestructura , Proteínas Mitocondriales/metabolismo , Mitofagia , Miocardio/metabolismo , Miocardio/ultraestructura , Fosforilación , Estado Prediabético/fisiopatología , Ratas , Ratas Long-Evans , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Sarcolema , Serina-Treonina Quinasas TOR/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Presión Ventricular
3.
J Cell Biol ; 217(6): 2205-2221, 2018 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-29650776

RESUMEN

Lymphatic endothelial cells (LECs) release extracellular chemokines to guide the migration of dendritic cells. In this study, we report that LECs also release basolateral exosome-rich endothelial vesicles (EEVs) that are secreted in greater numbers in the presence of inflammatory cytokines and accumulate in the perivascular stroma of small lymphatic vessels in human chronic inflammatory diseases. Proteomic analyses of EEV fractions identified >1,700 cargo proteins and revealed a dominant motility-promoting protein signature. In vitro and ex vivo EEV fractions augmented cellular protrusion formation in a CX3CL1/fractalkine-dependent fashion and enhanced the directional migratory response of human dendritic cells along guidance cues. We conclude that perilymphatic LEC exosomes enhance exploratory behavior and thus promote directional migration of CX3CR1-expressing cells in complex tissue environments.


Asunto(s)
Movimiento Celular , Células Dendríticas/citología , Células Dendríticas/metabolismo , Exosomas/metabolismo , Vasos Linfáticos/metabolismo , Animales , Línea Celular Tumoral , Extensiones de la Superficie Celular/metabolismo , Microambiente Celular , Quimiocina CX3CL1/metabolismo , Colágeno/metabolismo , Señales (Psicología) , Células Endoteliales/metabolismo , Células Endoteliales/ultraestructura , Exosomas/ultraestructura , Humanos , Inflamación/patología , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteómica , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo
4.
Br J Pharmacol ; 175(18): 3713-3726, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29971762

RESUMEN

BACKGROUND AND PURPOSE: Incidence and severity of obesity are increasing worldwide, however, efficient and safe pharmacological treatments are not yet available. Certain MAO inhibitors reduce body weight, although their effects on metabolic parameters have not been investigated. Here, we have assessed effects of a widely used, selective MAO-B inhibitor, selegiline, on metabolic parameters in a rat model of diet-induced obesity. EXPERIMENTAL APPROACH: Male Long-Evans rats were given control (CON) or a high-fat (20%), high-sucrose (15%) diet (HFS) for 25 weeks. From week 16, animals were injected s.c. with 0.25 mg·kg-1 selegiline (CON + S and HFS + S) or vehicle (CON, HFS) once daily. Whole body, subcutaneous and visceral fat was measured by CT, and glucose and insulin tolerance were tested. Expression of glucose transporters and chemokines was assessed by quantitative RT-PCR. KEY RESULTS: Selegiline decreased whole body fat, subcutaneous- and visceral adiposity, measured by CT and epididymal fat weight in the HFS group, compared with HFS placebo animals, without influencing body weight. Oral glucose tolerance and insulin tolerance tests showed impaired glucose homeostasis in HFS and HFS + S groups, although insulin levels in plasma and pancreas were unchanged. HFS induced expression of Srebp-1c, Glut1 and Ccl3 in adipose tissue, which were alleviated by selegiline. CONCLUSIONS AND IMPLICATIONS: Selegiline reduced adiposity, changes in adipose tissue energy metabolism and adipose inflammation induced by HFS diet without affecting the increased body weight, impairment of glucose homeostasis, or behaviour. These results suggest that selegiline could mitigate harmful effects of visceral adiposity.


Asunto(s)
Adiposidad/efectos de los fármacos , Dieta Alta en Grasa , Sacarosa en la Dieta/administración & dosificación , Inhibidores de la Monoaminooxidasa/farmacología , Selegilina/farmacología , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Quimiocina CCL3/genética , Ingestión de Energía , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/genética , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Proteínas de la Membrana/genética , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Long-Evans , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Sístole
5.
Thromb Haemost ; 117(2): 325-338, 2017 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-27853810

RESUMEN

Cell accumulation is a prerequisite for adipose tissue inflammation. The leukocyte integrin Mac-1 (CD11b/CD18, αMß2) is a classic adhesion receptor critically regulating inflammatory cell recruitment. Here, we tested the hypothesis that a genetic deficiency and a therapeutic modulation of Mac-1 regulate adipose tissue inflammation in a mouse model of diet-induced obesity (DIO). C57Bl6/J mice genetically deficient (Mac-1-/-) or competent for Mac-1 (WT) consumed a high fat diet for 20 weeks. Surprisingly, Mac-1-/- mice presented with increased diet-induced weight gain, decreased insulin sensitivity in skeletal muscle and in the liver in insulin-clamps, insulin secretion deficiency and elevated glucose levels in fasting animals, and dyslipidaemia. Unexpectedly, accumulation of adipose tissue macrophages (ATMs) was unaffected, while gene expression indicated less inflamed adipose tissue and macrophages in Mac-1-/- mice. In contrast, inflammatory gene expression at distant locations, such as in skeletal muscle, was not changed. Treatment of ATMs with an agonistic anti-Mac-1 antibody, M1/70, induced pro-inflammatory genes in cell culture. In vivo, treatment with M1/70 induced a hyper-inflammatory phenotype with increased expression of IL-6 and MCP-1, whereas accumulation of ATMs did not change. Finally, inhibition of Mac-1's adhesive interaction to CD40L by the peptide inhibitor cM7 did not affect myeloid cell accumulation in adipose tissue. We present the surprising finding that adhesive properties of the leukocyte integrin Mac-1 are not required for macrophage accumulation in adipose tissue. Instead, Mac-1 modulates inflammatory gene expression in macrophages. These findings question the net effect of integrin blockade in cardio-metabolic disease.


Asunto(s)
Antígeno CD11b/metabolismo , Antígenos CD18/metabolismo , Quimiotaxis , Dieta/efectos adversos , Inflamación/metabolismo , Grasa Intraabdominal/metabolismo , Leucocitos/metabolismo , Antígeno de Macrófago-1/metabolismo , Macrófagos/metabolismo , Obesidad/metabolismo , Transducción de Señal , Animales , Anticuerpos Monoclonales/farmacología , Antígeno CD11b/deficiencia , Antígeno CD11b/genética , Antígenos CD18/deficiencia , Antígenos CD18/genética , Adhesión Celular , Células Cultivadas , Quimiotaxis/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Genotipo , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Inflamación/genética , Inflamación/patología , Resistencia a la Insulina , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/patología , Leucocitos/efectos de los fármacos , Leucocitos/patología , Antígeno de Macrófago-1/genética , Macrófagos/efectos de los fármacos , Macrófagos/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/genética , Obesidad/patología , Fenotipo , Transducción de Señal/efectos de los fármacos , Aumento de Peso
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