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  • ACTIVATION  (9)
  • 1
    Keywords: PROTEIN ; MICE ; ACTIVATION ; PROGRESSION ; inactivation ; NEPHROPATHY ; 2 PARTS ; MANNOSE-BINDING LECTIN ; VASCULAR COMPLICATIONS ; CD59
    Abstract: Coagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM's lectin like domain dampens complement activation, while its EGF-like domains independently enhance activation of the anti-coagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating complement. Diabetic nephropathy was analysed in mice lacking TM's lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 mug/mg vs. 166 mug/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeD mice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeD mice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeD mice (e.g. albuminuria 85 mug/mg vs. 290 mug/mg, p〈0.001). In vitro TM's lectin-like domain cell-autonomously prevented glucose-induced complement activation on endothelial cells and - notably - on podocytes. Podocyte injury, which was enhanced in diabetic TMLeD/LeD mice, was reduced following complement inhibition with enoxaparin. The current study identifies a novel mechanism regulating complement activation in diabetic nephropathy. TM's lectin-like domain constrains glucose-induced complement activation on endothelial cells and podocytes and ameliorates albuminuria and glomerular damage in mice.
    Type of Publication: Journal article published
    PubMed ID: 23014597
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  • 2
    Keywords: RECEPTOR ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; PROTECTION ; CELL ; Germany ; MODEL ; MODELS ; NF-KAPPA-B ; ACTIVATION ; CELL ACTIVATION ; MECHANISM ; TRANSCRIPTION FACTOR ; mechanisms ; DELETION ; STEPS ; SIGNALING PATHWAYS ; PRODUCT ; SUPERFAMILY ; innate immunity ; Jun ; SOLUBLE RECEPTOR ; immune response ; IMMUNE-RESPONSE ; RECEPTORS ; INITIATION ; inflammation ; ANIMAL-MODELS ; immunoglobulin ; PRODUCTS ; LEADS ; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ; pattern recognition ; CLASS-III REGION ; DIABETIC VASCULOPATHY ; INFLAMMATORY RESPONSES
    Abstract: While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation
    Type of Publication: Journal article published
    PubMed ID: 15173891
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  • 3
    Keywords: IN-VITRO ; IN-VIVO ; PATHWAY ; VITRO ; DISEASE ; PROTEIN ; SURGERY ; MICE ; ACTIVATION ; COMPLEX ; MECHANISM ; cytokines ; PLASMA ; RAGE ; inflammation ; INJURY ; signaling ; CYTOKINE ; GENOTYPE ; toll-like receptor 4 ; INVESTIGATE ; sepsis ; TLR2 ; toll-like receptor 2 ; HMGB-1 ; HMGB1 ; host defense ; receptor for advanced glycation end products
    Abstract: High-mobility group box 1 (HMGB-1) has been reported as a "late" proinflammatory mediator in sepsis. In vitro data have shown that HMGB-1 can induce activation of intracellular signaling pathways via interaction with at least three pattern recognition receptors: Toll-like receptor (TLR) 2, TLR-4, and the receptor for advanced glycation end products (RAGE). The objective of this study was to investigate the role of these receptors in the in vivo response to HMGB-1. Therefore, we first performed a time-series experiment with wild-type (Wt) mice. High-mobility group box 1 induced time-dependent elevations of TNF-alpha, IL-6, monocyte chemoattractant protein 1, and thrombin-antithrombin complex levels in peritoneal lavage fluid and plasma. This inflammatory reaction was accompanied by a prominent and sustained rise in neutrophil counts in the peritoneal cavity. We next administered HMGB-1 to Wt, TLR-2(-/-), TLR-4(-/-), and RAGE(-/-) mice. All genotypes showed similar plasma levels of TNF-alpha, IL-6, IL-10, and thrombin-antithrombin complex at 2 h after intraperitoneal injection of HMGB-1. Compared with Wt mice, both TLR-4(-/-) and RAGE(-/-) mice displayed lower TNIF-alpha and IL-6 concentrations and lower neutrophil numbers in their peritoneal lavage fluid. In contrast, TLR-2(-/-) mice showed increased levels of TNF-alpha and IL-6 in their peritoneal cavity relative to Wt mice. These data indicate that HMGB-1 induces release of cytokines, activation of coagulation, and neutrophil recruitment in vivo via a mechanism that at least in part depends on TLR-4 and RAGE
    Type of Publication: Journal article published
    PubMed ID: 19218854
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; INHIBITION ; GENE ; GENE-EXPRESSION ; MICE ; TIME ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; TRANSCRIPTION FACTOR ; INDUCTION ; gene expression ; FIBER ; PRODUCT ; LIGANDS ; SUPERFAMILY ; GLYCATION END-PRODUCTS ; PROGRAMMED CELL-DEATH ; ALPHA-LIPOIC ACID ; microenvironment ; PAIN ; EPSILON-CARBOXYMETHYLLYSINE ; immunoglobulin ; NEUROPATHY ; OXIDATIVE-STRESS ; PERIPHERAL-NERVE ; PRODUCTS
    Abstract: Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-kappaB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-kappaBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-kappaB and NF-kappaB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-kappaB activation was blunted in RAGE-null (RAGE(-/-)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(-/-) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches
    Type of Publication: Journal article published
    PubMed ID: 15599399
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  • 5
    Keywords: RECEPTOR ; INHIBITOR ; INVASION ; SURVIVAL ; tumor ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; PATHWAY ; VIVO ; MICE ; TIME ; NF-KAPPA-B ; ACTIVATION ; MECHANISM ; animals ; mechanisms ; BINDING ; cytokines ; STIMULATION ; NO ; CARE ; DESIGN ; DIFFERENCE ; NECROSIS-FACTOR-ALPHA ; BETA ; FACTOR-KAPPA-B ; LETHALITY ; INHIBITORS ; FACTOR-ALPHA ; CYTOKINE ; PANCREATITIS ; INTERLEUKIN-1 ; NUCLEAR ; USA ; prospective ; animal ; NICOTINE ; MEDICINE ; response ; INTERVENTIONS ; LIGATION ; cecal ligation and puncture ; cholinergic anti-inflammatory pathway ; CHOLINERGIC ANTIINFLAMMATORY PATHWAY ; MURINE ENDOTOXEMIA ; neostigmine ; neutrophil ; physostigmine ; SEPTIC SHOCK ; SYSTEMIC INFLAMMATORY RESPONSE ; VAGUS NERVE
    Abstract: Objective: Lethal sepsis occurs when an excessive inflammatory response evolves that cannot be controlled by physiologic anti-inflammatory mechanisms, such as the recently described cholinergic anti-inflammatory pathway. Here we studied whether the cholinergic anti-inflammatory pathway can be activated by pharmacologic cholinesterase inhibition in vivo. Design: Prospective, randomized laboratory investigation that used an established murine sepsis model. Setting: Research laboratory in a university hospital. Subjects: Female C57BL/6 mice. Interventions: Sepsis in mice was induced by cecal ligation and puncture. Animals were treated immediately with intraperitoneal injections of nicotine (400 mu g/kg), physostigmine (80 mu g/kg), neostigmine (80 mu g/kg), or solvent three times daily for 3 days. Measurements and Main Results: Treatment with physostigmine significantly reduced lethality (p 〈= .01) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine (p 〈= .05). Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-kappa B (p 〈= .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-alpha., interleukin-1 beta, and interleukin-6 (p 〈= .001), and pulmonary neutrophil invasion (p 〈= .05). Animals treated with the peripheral cholinesterase inhibitor neostigmine showed no difference compared with physostigmine-treated animals. Conclusions: Our results demonstrate that cholinesterase inhibitors can be used successfully in the treatment of sepsis in a murine model and may be of interest for clinical use
    Type of Publication: Journal article published
    PubMed ID: 18091537
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  • 6
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH-FACTOR ; BLOOD ; SUPPORT ; GENE-EXPRESSION ; TISSUE ; ACCUMULATION ; MICE ; ACTIVATION ; INJURIES ; LIGAND ; MESANGIAL CELLS ; MEMBER ; MOUSE ; AMPLIFICATION ; AGE ; SUPERFAMILY ; EPITHELIAL-CELLS ; BINDING-PROTEINS ; APOLIPOPROTEIN-E ; PROTEIN-KINASE-C ; GLUCOSE ; VESSELS ; ALDOSE REDUCTASE ; GLYCOSYLATION END-PRODUCTS ; OXIDANT STRESS ; PKC-BETA INHIBITOR
    Abstract: Receptor for advanced glycation endproducts (RAGE) is a multi- ligand member of the immunoglobulin superfamily of cell surface molecules. Driven by rapid accumulation and expression of key ligands such as advanced glycation endproducts (AGE) and S100/calgranulins in diabetic tissues, upregulation and activation of RAGE magnifies cellular perturbation in tissues affected by hyperglycemia, such as the large blood vessels and the kidney. In the diabetic glomerulus, RAGE is expressed principally by glomerular visceral epithelial cells (podocytes). Blockade of RAGE in the hyperglycemic db/db mouse suppresses functional and structural alterations in the kidney, in the absence of alterations in blood glucose. Recent studies in homozygous RAGE null mice support a key role for RAGE in glomerular perturbation in diabetes. Importantly, beyond diabetes, studies in other settings of glomerulopathies support a critical RAGE-dependent pathway in podocytes linked to albuminuria, mesangial expansion, and glomerular sclerosis. A new paradigm is propsed in glomerular injury, and it is suggested that blockade of the RAGE axis may provide a novel means to prevent irreparable glomerular injury in diabetes and other sclerosing glomerulopathies
    Type of Publication: Journal article published
    PubMed ID: 12707408
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  • 7
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; ENDOTHELIAL GROWTH-FACTOR ; NEW-YORK ; ACCUMULATION ; MICE ; TIME ; ACTIVATION ; MESANGIAL CELLS ; renal function ; RENAL-FUNCTION ; mechanisms ; MEMBRANE ; AGE ; PATHOGENESIS ; DISPLAY ; BINDING-PROTEINS ; GLYCATION END-PRODUCTS ; GROWTH-FACTOR-BETA ; pathology ; PROGRESSIVE NEPHROPATHIES ; OXIDANT STRESS ; CELL-SURFACE RECEPTOR ; FACTOR-BETA ; MATRIX GENE-EXPRESSION ; PASSIVE HEYMANN NEPHRITIS
    Abstract: 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
    Type of Publication: Journal article published
    PubMed ID: 12651605
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  • 8
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; KINASE ; MODEL ; PATHWAY ; PATHWAYS ; VOLUME ; DEATH ; transcription ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; INDUCTION ; CONTRAST ; DENDRITIC CELLS ; LYMPH-NODES ; SIGNAL ; FORM ; DIFFERENCE ; CELL-DEATH ; SIGNALING PATHWAYS ; MIGRATION ; ONCOGENE ; ATHEROSCLEROSIS ; immune response ; IMMUNE-RESPONSE ; PERIPHERAL-BLOOD ; CD4(+) T-CELLS ; F ; AUTOIMMUNITY ; CYTOKINE ; PERSISTENT ; NODES ; RE ; STRENGTH ; CD40 LIGAND ; CD40-CD40 LIGAND ; IL-12 PRODUCTION ; PHYSIOLOGICAL STIMULI
    Abstract: Migration to lymph nodes and secretion of cytokines are critical functions of mature dendritic cells (DCs); however, these 2 functions are not necessarily linked. This is the first report showing that quantitative differences in identical signaling pathways determine DC migration and cytokine secretion. Using different polymerized forms of CD40 ligand, we demonstrate that the strength and persistence of CD40 signaling can induce either function. Induction of monocyte-derived DC (MoDC) migration required a weak and transient CD40 signal, whereas strong and persistent CD40 signaling blocked migration and biased toward cytokine secretion. In contrast to MoDCs, CD40 activation of CD1c(+) peripheral blood DCs (PBDCs) induced a nonpersistent, intracellular signaling profile resulting in migratory-type DCs unable to secrete interleukin-12p70 (IL-12p70). Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38K activation synergistically mediated cytokine secretion, whereas migration was enhanced by p38K activation but reduced by persistent ERK1/2 activity. This model of signal strength and persistence also applied when stimulating DCs with intact microbes. Thus, a novel concept emerges in which the type of immune response induced by DCs is tuned by the strength and persistence of DC activating signals. (C) 2004 by The American Society of Hematology
    Type of Publication: Journal article published
    PubMed ID: 15113760
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  • 9
    Keywords: EXPRESSION ; ACTIVATION ; BLOOD-FLOW ; RAT ; inactivation ; NEURONS ; FOREBRAIN ; GLYOXALASE-I ; PERIPHERAL NEUROPATHY ; RESISTANT SODIUM-CHANNELS ; ROOT GANGLION NEURONS ; SENSITIVE METHOD
    Abstract: This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal-and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy
    Type of Publication: Journal article published
    PubMed ID: 22581285
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