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Background: Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive, and uniformly fatal neurodegenerative disease. The reported incidence of CJD is 1 to 2 per million people worldwide annually, with fewer than 1,000 cases in the United States per year. In this study, we report a unique case series on temporo-spatial clusters of CJD cases in West Michigan. Methods: A total of five CJD cases consisting of two temporal clusters were seen from July 2021 to June 2022 at Corewell Health West hospitals. All patients had brain MRI, EEG, and CSF tests. Four patients underwent autopsies. Results: All patients' MRIs showed characteristic CJD patterns. Four patients had positive CJD panels in CSF. One patient had typical CJD EEG findings. Four patients were confirmed as sporadic CJD by autopsy. All patients died within 3 months after CJD was suspected. Discussion: All patients lived within a 90-mile radius of Grand Rapids, MI, and two lived in the same county. West Michigan has a population of 1.6 million people, and the four counties where five patients lived have a combined population of 395,104, indicating CJD's new case rate of 3.1 and 12.5 per million people, respectively. Corewell Health is one of the three major healthcare systems in West Michigan. The actual incidence of CJD in West Michigan is likely even higher. This dense temporal and spatial cluster of CJD cases poses a serious public health challenge and warrants urgent investigation.
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OBJECTIVE: Heightened expression of the receptor for advanced glycation end products (RAGE) contributes to development of systemic diabetic complications, but its contribution to diabetic neuropathy is uncertain. We studied experimental diabetic neuropathy and its relationship with RAGE expression using streptozotocin-induced diabetic mice including a RAGE(-/-) cohort exposed to long-term diabetes compared with littermates without diabetes. RESEARCH DESIGN AND METHODS: Structural indexes of neuropathy were addressed with serial (1, 3, 5, and 9 months of experimental diabetes) electrophysiological and quantitative morphometric analysis of dorsal root ganglia (DRG), peripheral nerve, and epidermal innervation. RAGE protein and mRNA levels in DRG, peripheral nerve, and epidermal terminals were assessed in WT and RAGE(-/-) mice, with and without diabetes. The correlation of RAGE activation with nuclear factor (NF)-kappaB and protein kinase C beta II (PKC beta II) protein and mRNA expression was also determined. RESULTS: Diabetic peripheral epidermal axons, sural axons, Schwann cells, and sensory neurons within ganglia developed dramatic and cumulative rises in RAGE mRNA and protein along with progressive electrophysiological and structural abnormalities. RAGE(-/-) mice had attenuated structural features of neuropathy after 5 months of diabetes. RAGE-mediated signaling pathway activation for NF-kappaB and PKC beta II pathways was most evident among Schwann cells in the DRG and peripheral nerve. CONCLUSIONS: In a long-term model of experimental diabetes resembling human diabetic peripheral neuropathy, RAGE expression in the peripheral nervous system rises cumulatively and relates to progressive pathological changes. Mice lacking RAGE have attenuated features of neuropathy and limited activation of potentially detrimental signaling pathways.
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Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/fisiopatología , Receptores Inmunológicos/metabolismo , Nervio Ciático/fisiopatología , Animales , Glucemia/metabolismo , Cruzamientos Genéticos , Diabetes Mellitus Experimental/metabolismo , Neuropatías Diabéticas/sangre , Progresión de la Enfermedad , Ganglios Espinales/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Conducción Nerviosa , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/deficienciaRESUMEN
Previous studies demonstrated that induction of diabetes with streptozotocin (stz) accelerated atherosclerosis in hyperlipidemic apo E null (-/-) mice. Blockade of the Receptor for Advanced Glycation Endproducts (RAGE) in those animals suppressed acceleration of atherosclerotic lesion area, in a manner independent of changes in levels of glucose, insulin or lipids. In the present studies, we extended these concepts to a murine model of type 2 diabetes, and bred apo E -/- mice into the db/db background. Db/db mice are a model of obesity and insulin resistance-mediated hyperglycemia. Compared to apo E -/- m/db (non-diabetic) mice, apo E -/- db/db (diabetic) mice displayed accelerated atherosclerosis at the aortic sinus. Consistent with an important role for RAGE in this process, administration of soluble (s) RAGE, the extracellular ligand-binding domain of RAGE, resulted in significantly reduced atherosclerotic lesion area in a glycemia- and lipid-independent manner. In parallel, apo E -/- db/db mice displayed RAGE-dependent enhanced expression of Vascular Cell Adhesion Molecule-1, tissue factor and matrix metalloproteinase (MMP)-9 antigen/activity in aortae compared to non-diabetic animals. In addition, consistent with the premise that upregulation of RAGE ligands and RAGE occurs even in the non-diabetic, hyperlipidemic state, albeit to lesser degrees than in diabetes, administration of sRAGE to apo E -/- m/db mice resulted in decreased atherosclerotic lesion area at the aortic sinus. Taken together, these findings establish a new murine model for the study of atherosclerosis in type 2 diabetes and highlight important roles for RAGE in proatherogenic mechanisms in hyperglycemia triggered by insulin resistance.
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Arteritis/etiología , Aterosclerosis/etiología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Receptores Inmunológicos/administración & dosificación , Animales , Aorta Torácica/metabolismo , Aorta Torácica/patología , Arteritis/metabolismo , Arteritis/prevención & control , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Productos Finales de Glicación Avanzada/administración & dosificación , Productos Finales de Glicación Avanzada/metabolismo , Immunoblotting , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/metabolismo , Resultado del Tratamiento , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
The major consequence of long-term diabetes is the increased incidence of disease of the vasculature. Of the underlying mechanisms leading to disease, the accumulation of advanced glycation end products (AGEs), resulting from the associated hyperglycemia, is the most convincing. Interaction of AGEs with their receptor, RAGE, activates numerous signaling pathways leading to activation of proinflammatory and procoagulatory genes. Studies in rodent models of macro- and microvascular disease have demonstrated that blockade of RAGE can prevent development of disease. These observations highlight RAGE as a therapeutic target for treatment of diabetic vascular disease.
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Angiopatías Diabéticas/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Angiopatías Diabéticas/tratamiento farmacológico , Angiopatías Diabéticas/patología , Progresión de la Enfermedad , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Hiperglucemia/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Transducción de SeñalRESUMEN
Many studies have suggested that the expression of RAGE (receptor for advanced glycation end products) is upregulated in human tissues susceptible to the long-term complications of diabetes. From the kidneys to the macrovessels of the aorta, RAGE expression is upregulated in a diverse array of cell types, from glomerular epithelial cells (podocytes) to endothelial cells, vascular smooth muscle cells, and inflammatory mononuclear phagocytes and lymphocytes. Although RAGE was first described as a receptor for advanced glycation end products (AGEs), the key finding that RAGE was also a signaling receptor for proinflammatory S100/calgranulins and amphoterin, led to the premise that even in euglycemia, ligand-RAGE interaction propagated inflammatory mechanisms linked to chronic cellular perturbation and tissue injury. Indeed, such considerations suggested that RAGE might even participate in the pathogenesis of type 1 diabetes. Our studies have shown that pharmacological and/or genetic deletion/mutation of the receptor attenuates the development of hyperglycemia in NOD mice; in mice with myriad complications of diabetes, interruption of ligand-RAGE interaction prevents or delays the chronic complications of the disease in both macro- and microvessel structures. Taken together, these findings suggest that RAGE is "at the right place and time" to contribute to the pathogenesis of diabetes and it complications. Studies are in progress to test the premise that antagonism of this interaction is a logical strategy for the prevention and treatment of diabetes.
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Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus/fisiopatología , Receptores Inmunológicos/fisiología , Animales , Arterias/lesiones , Arterias/patología , Arteriosclerosis/fisiopatología , Angiopatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Humanos , Inflamación/fisiopatología , Ratones , Ratones Endogámicos NOD , Receptor para Productos Finales de Glicación Avanzada , Enfermedades Vasculares/fisiopatologíaRESUMEN
PURPOSE: The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. This study was conducted to characterize the role of the RAGE axis in a murine model of nonproliferative diabetic retinopathy (NPDR). METHODS: The retinas of hyperglycemic, hyperlipidemic (HGHL, apolipoprotein E(-/-) db/db) mice were examined for the development of early retinal vascular lesions of NPDR and compared to littermates at 6 months of age. Neural function was assessed with electroretinography. Immunohistochemistry, real-time RT-PCR, autofluorescence, and ELISA studies were used to localize and quantify the AGE/RAGE axis. Soluble RAGE, a competitor of cellular RAGE for its ligands, was administered to assess the impact of RAGE blockade. RESULTS: Early inner retinal neuronal dysfunction, manifested by prolonged latencies of the oscillatory potentials and b-wave, was detected in hyperglycemic mice. HGHL mice exhibited accelerated development of acellular capillaries and pericyte ghosts compared with littermate control animals. AGEs were localized primarily to the vitreous cavity and internal limiting membrane (ILM) of the retina, where they were intimately associated with the footplates of RAGE-expressing Müller cells. AGE accumulation measured by ELISA was increased within the retinal extracellular matrix of hyperglycemic mice. AGE fluorescence and upregulation of RAGE transcripts was highest in the retinas of HGHL mice, and attenuation of the RAGE axis with soluble RAGE ameliorated neuronal dysfunction and reduced the development of capillary lesions in these mice. CONCLUSIONS: In early diabetic retinopathy, the RAGE axis, comprising the cellular receptor and its AGE ligands, is amplified within the retina and is accentuated along the vitreoretinal interface. Antagonism of the RAGE axis in NPDR reduces neurovascular perturbations, providing an important therapeutic target for intervention.
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Apolipoproteínas E/metabolismo , Retinopatía Diabética/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Hiperglucemia/metabolismo , Hiperlipidemias/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Retinopatía Diabética/fisiopatología , Electrorretinografía , Ensayo de Inmunoadsorción Enzimática , Femenino , Fluorescencia , Técnica del Anticuerpo Fluorescente Indirecta , Expresión Génica , Productos Finales de Glicación Avanzada/genética , Hiperglucemia/patología , Hiperlipidemias/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/genética , Vasos Retinianos/patología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The exquisite ability of the liver to regenerate is finite. Identification of mechanisms that limit regeneration after massive injury holds the key to expanding the limits of liver transplantation and salvaging livers and hosts overwhelmed by carcinoma and toxic insults. Receptor for advanced glycation endproducts (RAGE) is up-regulated in liver remnants selectively after massive (85%) versus partial (70%) hepatectomy, principally in mononuclear phagocyte-derived dendritic cells (MPDDCs). Blockade of RAGE, using pharmacological antagonists or transgenic mice in which a signaling-deficient RAGE mutant is expressed in cells of mononuclear phagocyte lineage, significantly increases survival after massive liver resection. In the first hours after massive resection, remnants retrieved from RAGE-blocked mice displayed increased activated NF-kappaB, principally in hepatocytes, and enhanced expression of regeneration-promoting cytokines, TNF-alpha and IL-6, and the antiinflammatory cytokine, IL-10. Hepatocyte proliferation was increased by RAGE blockade, in parallel with significantly reduced apoptosis. These data highlight central roles for RAGE and MPDDCs in modulation of cell death-promoting mechanisms in massive hepatectomy and suggest that RAGE blockade is a novel strategy to promote regeneration in the massively injured liver.
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Regeneración Hepática , Hígado/metabolismo , Hígado/patología , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Apoptosis/fisiología , Linaje de la Célula , Proliferación Celular , Citocinas/metabolismo , Regulación de la Expresión Génica , Hepatectomía , Humanos , Hígado/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos , Tasa de SupervivenciaRESUMEN
The Receptor for Advanced Glycation End Products (RAGE) is a multiligand member of the immunoglobulin superfamily. RAGE interacts with AGEs, the products of nonenzymatic glycation/oxidation of proteins and lipids that accumulate in diverse settings, such as diabetes, inflammation, renal failure, pro-oxidant states and natural aging. In addition, RAGE is also a receptor for amyloid-beta peptide and beta-sheet fibril species. Recent studies underscore the premise that RAGE interacts with pro-inflammatory molecules, including S100/calgranulins and amphoterin, the latter also known as high mobility group box 1 (HMGB1). In chronic neurodegenerative disorders as well as in nerve tissue upon acute injury, evidence points to upregulation of both RAGE and these ligand families. In this review, we will discuss the implications of transient/self-limited upregulation of RAGE and its ligands, vs sustained/chronic upregulation of this axis in neurodegeneration vs repair in both the central and peripheral nervous systems. Experimental evidence supports the premise that RAGE bears both homeostatic and injurious properties in the nervous system, thereby highlighting "yin/yang" features of this receptor and its ligand families.
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Complicaciones de la Diabetes/complicaciones , Complicaciones de la Diabetes/metabolismo , Enfermedades Neurodegenerativas/etiología , Receptores Inmunológicos/metabolismo , Cicatrización de Heridas/fisiología , Animales , Productos Finales de Glicación Avanzada/metabolismo , Proteína HMGB1/metabolismo , Humanos , Complejo de Antígeno L1 de Leucocito/metabolismo , Modelos Biológicos , Enfermedades Neurodegenerativas/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Proteínas S100/metabolismo , Estrés Fisiológico/metabolismoRESUMEN
Axotomy of peripheral nerve triggers events that coordinate a limited inflammatory response to axonal degeneration and initiation of neurite outgrowth. Inflammatory and neurite outgrowth-promoting roles for the receptor for advanced glycation end products (RAGE) have been suggested, so we tested its role in peripheral nerve regeneration. Analysis of immunohistochemical localization of RAGE by confocal microscopy revealed that RAGE was expressed in axons and infiltrating mononuclear phagocytes upon unilateral sciatic nerve crush in mice. Administration of soluble RAGE, the extracellular ligand binding domain of RAGE, or blocking F(ab')2 fragments of antibodies raised to either RAGE or its ligands, S100/calgranulins or amphoterin, reduced functional recovery as assessed by motor and sensory nerve conduction velocities and sciatic functional index and reduced regeneration, as assessed by myelinated fiber density after acute crush of the sciatic nerve. In parallel, in mice subjected to RAGE blockade, decreased numbers of mononuclear phagocytes infiltrated the distal nerve segments after crush. These findings provide the first evidence of an innate function of the ligand/RAGE axis and suggest that RAGE plays an important role in regeneration of the peripheral nervous system.
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Regeneración Nerviosa , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/fisiología , Nervio Ciático/lesiones , Animales , Anticuerpos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Compresión Nerviosa , Regeneración Nerviosa/efectos de los fármacos , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/inmunología , Nervio Ciático/citología , Nervio Ciático/fisiologíaRESUMEN
Axotomy of peripheral nerve stimulates events in multiple cell types that initiate a limited inflammatory response to axonal degeneration and simultaneous outgrowth of neurites into the distal segments after injury. We found that pharmacological blockade of RAGE impaired peripheral nerve regeneration in mice subjected to RAGE blockade and acute crush of the sciatic nerve. As our studies revealed that RAGE was expressed in axons and in infiltrating mononuclear phagocytes upon injury, we tested the role of RAGE in these distinct cell types on nerve regeneration. Transgenic mice expressing signal transduction-deficient RAGE in mononuclear phagocytes or peripheral neurons were generated and subjected to unilateral crush injury to the sciatic nerve. Transgenic mice displayed decreased functional and morphological recovery compared with littermate controls, as assessed by motor and sensory conduction velocities; and myelinated fiber density. In double transgenic mice expressing signal transduction deficient RAGE in both mononuclear phagocytes and peripheral neurons, regeneration was even further impaired, suggesting the critical interplay between RAGE-modulated inflammation and neurite outgrowth in nerve repair. These findings suggest that RAGE signaling in inflammatory cells and peripheral neurons plays an important role in plasticity of the peripheral nervous system.
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Regeneración Nerviosa , Neuronas/fisiología , Fagocitos/fisiología , Receptores Inmunológicos/fisiología , Nervio Ciático/lesiones , Animales , Movimiento Celular , Proteínas de Unión al ADN/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación , Compresión Nerviosa , Regeneración Nerviosa/inmunología , Neuritas/ultraestructura , Neuronas/metabolismo , Fagocitos/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/genética , Factor de Transcripción STAT3 , Nervio Ciático/citología , Nervio Ciático/fisiología , Transducción de Señal , Transactivadores/metabolismoRESUMEN
Porphyromonas gingivalis is an etiologic agent of periodontal disease in humans, which has been linked to an increased risk for atherosclerosis-related events. In this study, we examined the effect of P. gingivalis infection on human macrophages with respect to foam cell formation, the hallmark of early atherogenesis, and the potential of P. gingivalis to induce its uptake by these cells. Human monocyte-derived macrophages were incubated with low density lipoprotein and infected with P. gingivalis FDC381 or its fimbriae deficient mutant, DPG3. Consistent with a role for fimbriae in this process, strain 381 significantly increased foam cell formation as compared to DPG3. Recovery of viable P. gingivalis in antibiotic protection experiments was significantly higher for strain 381 than for DPG3. By transmission electron microscopy, the wild-type strain was shown to adhere to and enter THP-1 cells. These results suggest that properties of P. gingivalis which render it capable of adhering to/invading other cell types may also be operative in macrophages and play an important role in its atherogenic potential.
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Células Espumosas/fisiología , Macrófagos/microbiología , Porphyromonas gingivalis/fisiología , Células Cultivadas , Fimbrias Bacterianas/fisiología , Humanos , Lipoproteínas LDL/farmacologíaRESUMEN
Receptor for AGE (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Engagement of RAGE by its signal transduction ligands evokes inflammatory cell infiltration and activation in the vessel wall. In diabetes, when fueled by oxidant stress, hyperglycemia, and superimposed stresses such as hyperlipidemia or acute balloon/endothelial denuding arterial injury, the ligand-RAGE axis amplifies vascular stress and accelerates atherosclerosis and neointimal expansion. In this brief synopsis, we review the use of rodent models to test these concepts. Taken together, our findings support the premise that RAGE is an amplification step in vascular inflammation and acceleration of atherosclerosis. Future studies must rigorously test the potential impact of RAGE blockade in human subjects; such trials are on the horizon.
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Arteriosclerosis/metabolismo , Angiopatías Diabéticas/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Modelos Animales , Receptores Inmunológicos/fisiología , Vasculitis/metabolismo , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Arteriosclerosis/patología , Moléculas de Adhesión Celular/biosíntesis , Reestenosis Coronaria/etiología , Reestenosis Coronaria/metabolismo , Reestenosis Coronaria/patología , Citocinas/biosíntesis , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Angiopatías Diabéticas/patología , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Hiperlipidemias/sangre , Hiperlipidemias/complicaciones , Hiperlipidemias/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo , Ratas , Ratas Zucker , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Receptores Inmunológicos/uso terapéutico , Transducción de Señal , Solubilidad , Vasculitis/patologíaRESUMEN
The complications of diabetes are myriad and represent a rising cause of morbidity and mortality, particularly in the Western world. The update of the Diabetes Control and Clinical Trials Group/Epidemiology of Diabetes Interventions and Complications Research Group (DCCT/EDIC) suggested that previous strict control of hyperglycaemia was associated with reduced carotid atherosclerosis compared to conventional treatment, even after levels of glycosylated haemoglobin between the two treatment groups became indistinguishable. These intriguing findings prompt the key question, why does the blood vessel 'remember'? This review focuses on the hypothesis that the ligand/RAGE axis contributes importantly to glycaemic 'memory'. Studies in rodent models of diabetes suggest that blockade or genetic modification of RAGE suppress diabetes-associated progression of atherosclerosis, exaggerated neointimal expansion consequent to acute arterial injury, and cardiac dysfunction. We propose that therapeutic RAGE blockade will intercept maladaptive diabetes-associated memory in the vessel wall and provide cardiovascular protection in diabetes.
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Aterosclerosis/metabolismo , Complicaciones de la Diabetes/metabolismo , Angiopatías Diabéticas/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Arterias/metabolismo , Arterias/patología , Aterosclerosis/patología , Antígenos CD18/metabolismo , Complicaciones de la Diabetes/inmunología , Complicaciones de la Diabetes/patología , Angiopatías Diabéticas/patología , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Glucosa/metabolismo , Proteína HMGB1/metabolismo , Humanos , Hiperglucemia/metabolismo , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Complejo de Antígeno L1 de Leucocito/inmunología , Complejo de Antígeno L1 de Leucocito/metabolismo , Ligandos , Miocardio/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/genética , Transducción de SeñalRESUMEN
Cellular proliferation, migration, and expression of extracellular matrix proteins and MMPs contribute to neointimal formation upon vascular injury. Wild-type mice undergoing arterial endothelial denudation displayed striking upregulation of receptor for advanced glycation end products (RAGE) in the injured vessel, particularly in activated smooth muscle cells of the expanding neointima. In parallel, two of RAGE's signal transducing ligands, advanced glycation end products (AGEs) and S100/calgranulins, demonstrated increased deposition/expression in the injured vessel wall. Blockade of RAGE, employing soluble truncated receptor or antibodies, or in homozygous RAGE null mice, resulted in significantly decreased neointimal expansion after arterial injury and decreased smooth muscle cell proliferation, migration, and expression of extracellular matrix proteins. A critical role for smooth muscle cell RAGE signaling was demonstrated in mice bearing a transgene encoding a RAGE cytosolic tail-deletion mutant, specifically in smooth muscle cells, driven by the SM22alpha promoter. Upon arterial injury, neointimal expansion was strikingly suppressed compared with that observed in wild-type littermates. Taken together, these data highlight key roles for RAGE in modulating smooth muscle cell properties after injury and suggest that RAGE is a logical target for suppression of untoward neointimal expansion consequent to arterial injury.
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Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/fisiología , Túnica Íntima/citología , Animales , Arteriosclerosis , División Celular , Movimiento Celular , Células Cultivadas , Reestenosis Coronaria , Relación Dosis-Respuesta a Droga , Matriz Extracelular/metabolismo , Heterocigoto , Homocigoto , Immunoblotting , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Liso/citología , Pruebas de Precipitina , Regiones Promotoras Genéticas , ARN/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas S100/metabolismo , Transducción de Señal , Factores de Tiempo , Túnica Íntima/patología , Regulación hacia ArribaRESUMEN
Diabetic nephropathy ensues from events involving earliest changes in the glomeruli and podocytes, followed by accumulation of extracellular matrix in the mesangium. Postulated mechanisms include roles for vascular endothelial growth factor (VEGF), produced by podocytes and contributing to enhanced excretion of urinary albumin and recruitment/activation of inflammatory cells, and transforming growth factor-beta (TGF-beta), elicited largely from mesangial cells and driving production of extracellular matrix. RAGE, a receptor for advanced glycation endproducts (AGEs) and S100/calgranulins, displays enhanced expression in podocytes of genetically diabetic db/db mice by age 13 weeks. RAGE-bearing podocytes express high levels of VEGF by this time, in parallel with enhanced recruitment of mononuclear phagocytes to the glomeruli; events prevented by blockade of RAGE. By age 27 weeks, soluble RAGE-treated db/db mice displayed diminished albuminuria and glomerulosclerosis, and improved renal function. Diabetic homozygous RAGE null mice failed to develop significantly increased mesangial matrix expansion or thickening of the glomerular basement membrane. We propose that activation of RAGE contributes to expression of VEGF and enhanced attraction/activation of inflammatory cells in the diabetic glomerulus, thereby setting the stage for mesangial activation and TGF-beta production; processes which converge to cause albuminuria and glomerulosclerosis.
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Nefropatías Diabéticas/patología , Corteza Renal/patología , Receptores Inmunológicos/fisiología , Urotelio/patología , Albuminuria/patología , Animales , Diferenciación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Productos Finales de Glicación Avanzada/metabolismo , Masculino , Ratones , Ratones Mutantes , Receptor para Productos Finales de Glicación AvanzadaRESUMEN
BACKGROUND: Previous studies suggested that blockade of RAGE in diabetic apolipoprotein (apo) E-null mice suppressed early acceleration of atherosclerosis. A critical test of the potential applicability of RAGE blockade to clinical settings was its ability to impact established vascular disease. In this study, we tested the hypothesis that RAGE contributed to lesion progression in established atherosclerosis in diabetic apoE-null mice. METHODS AND RESULTS: Male apoE-null mice, age 6 weeks, were rendered diabetic with streptozotocin or treated with citrate buffer. At age 14 weeks, certain mice were killed or treated with once-daily murine soluble RAGE or albumin; all mice were killed at age 20 weeks. Compared with diabetic mice at age 14 weeks, albumin-treated animals displayed increased atherosclerotic lesion area and complexity. In diabetic mice treated with sRAGE from age 14 to 20 weeks, lesion area and complexity were significantly reduced and not statistically different from those observed in diabetic mice at age 14 weeks. In parallel, decreased parameters of inflammation and mononuclear phagocyte and smooth muscle cell activation were observed. CONCLUSIONS: RAGE contributes not only to accelerated lesion formation in diabetic apoE-null mice but also to lesion progression. Blockade of RAGE may be a novel strategy to stabilize atherosclerosis and vascular inflammation in established diabetes.