RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions

Chandna, Andrew R.; Nair, Manoj; Chang, C. Y.; Pennington, Paul R.; Yamamoto, Yasuhiko; Mousseau, Darrell D.; Campanucci, Verónica A.

doi:10.1111/ejn.12795

Cited by 14 publications

(19 citation statements)

References 61 publications

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“…To test the potential role of RAGE expression on CAP-evoked currents, we cultured lumbar DRG neurons from RAGE KO mice. In a previous study by Chandna et al [ 26 ] we worked with this particular transgenic mouse [ 25 ], and confirmed the lack of RAGE expression in various tissues, including the peripheral nervous system and lung. Cultured DRG neurons from RAGE KO mice had passive membrane properties ( Table 2 ) and CAP-evoked currents that were indistinguishable from those obtained from WT mice ( Fig 1 vs. Fig 5 ).…”

Section: Resultssupporting

confidence: 68%

“…To study the effect of high glucose on sensory neurons, we performed a series of experiments designed to evaluate the currents mediated by the transient receptor potential 1 (TRPV1). Neonatal mouse DRG neurons were maintained in either 5 mM of glucose (control) or 25mM of glucose (high glucose) for 1 week [ 26 , 28 ]. Under these experimental conditions, we used repetitive applications of the TRPV1 agonist capsaicin (CAP, 5 μM, at 30 s intervals), which normally causes a use-dependent rundown of CAP-evoked currents in the presence of Ca 2+ ions ( Fig 1A ) [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

“…Heterozygous mice generated from our breeding strategy were solely used as breeding animals and were not used for experimental purposes in this study. Mice were genotyped using genomic DNA and polymerase chain reaction as previously described [ 25 , 26 ]. Most experiments were done with neonatal pups (P0–P3), except those in which DRG neurons were cultured from 2-3-month-old mice.…”

Section: Methodsmentioning

confidence: 99%

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RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose

et al. 2018

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Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.

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Section: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose

et al. 2018

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“…Expression of RAGE is also associated with increased lung inflammation (11). It is interesting that the RAGE ligand HMGB1 may inactivate nicotinic acetylcholine receptors in certain neuronal cells (14). Moreover, nicotine treatment at very low doses decreased LPS-induced HMGB1 induction by increasing the nicotinic acetylcholine receptor and hemoxygenase in macrophages and protecting against experimental sepsis (70).…”

Section: Discussionmentioning

confidence: 99%

Acute pulmonary effects of aerosolized nicotine

Ahmad

Zafar

Mariappan

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

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Nicotine is a highly addictive principal component of both tobacco and electronic cigarette that is readily absorbed in blood. Nicotine-containing electronic cigarettes are promoted as a safe alternative to cigarette smoking. However, the isolated effects of inhaled nicotine are largely unknown. Here we report a novel rat model of aerosolized nicotine with a particle size (~1 μm) in the respirable diameter range. Acute nicotine inhalation caused increased pulmonary edema and lung injury as measured by enhanced bronchoalveolar lavage fluid protein, IgM, lung wet-to-dry weight ratio, and high-mobility group box 1 (HMGB1) protein and decreased lung E-cadherin protein. Immunohistochemical analysis revealed congested blood vessels and increased neutrophil infiltration. Lung myeloperoxidase mRNA and protein increased in the nicotine-exposed rats. Complete blood counts also showed an increase in neutrophils, white blood cells, eosinophils, and basophils. Arterial blood gas measurements showed an increase in lactate. Lungs of nicotine-inhaling animals revealed increased mRNA levels of IL-1A and CXCL1. There was also an increase in IL-1α protein. In in vitro air-liquid interface cultures of airway epithelial cells, there was a dose dependent increase in HMGB1 release with nicotine treatment. Air-liquid cultures exposed to nicotine also resulted in a dose-dependent loss of barrier as measured by transepithelial electrical resistance and a decrease in E-cadherin expression. Nicotine also caused a dose-dependent increase in epithelial cell death and an increase in caspase-3/7 activities. These results show that the nicotine content of electronic cigarettes may have adverse pulmonary and systemic effects.

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“…Autonomic dysfunction is a serious complication of diabetes and can lead to cardiovascular abnormalities. It could be triggered by advanced glycation end products and reactive oxygen species mediated inactivation of neuronal nicotinic acetylcholine receptors, impairing synaptic transmission in sympathetic ganglia and resulting in autonomic failure [ 69 ]. Myocardial down-regulation of Chrng and Chrna1 demonstrated in our present study might be another factor of cardiac autonomic dysfunction in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic alterations in the heart of non-obese type 2 diabetic Goto-Kakizaki rats

Sárközy

Szűcs

Fekete

et al. 2016

Cardiovasc Diabetol

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BackgroundThere is a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM) due to the worldwide obesity epidemic. However, a significant proportion of T2DM patients are non-obese and they also have an increased risk of cardiovascular diseases. As the Goto-Kakizaki (GK) rat is a well-known model of non-obese T2DM, the goal of this study was to investigate the effect of non-obese T2DM on cardiac alterations of the transcriptome in GK rats.MethodsFasting blood glucose, serum insulin and cholesterol levels were measured at 7, 11, and 15 weeks of age in male GK and control rats. Oral glucose tolerance test and pancreatic insulin level measurements were performed at 11 weeks of age. At week 15, total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 41,012 genes, and then expression of selected genes was confirmed by qRT-PCR. Gene ontology and protein–protein network analyses were performed to demonstrate potentially characteristic gene alterations and key genes in non-obese T2DM.ResultsFasting blood glucose, serum insulin and cholesterol levels were significantly increased, glucose tolerance and insulin sensitivity were significantly impaired in GK rats as compared to controls. In hearts of GK rats, 204 genes showed significant up-regulation and 303 genes showed down-regulation as compared to controls according to microarray analysis. Genes with significantly altered expression in the heart due to non-obese T2DM includes functional clusters of metabolism (e.g. Cyp2e1, Akr1b10), signal transduction (e.g. Dpp4, Stat3), receptors and ion channels (e.g. Sln, Chrng), membrane and structural proteins (e.g. Tnni1, Mylk2, Col8a1, Adam33), cell growth and differentiation (e.g. Gpc3, Jund), immune response (e.g. C3, C4a), and others (e.g. Lrp8, Msln, Klkc1, Epn3). Gene ontology analysis revealed several significantly enriched functional inter-relationships between genes influenced by non-obese T2DM. Protein–protein interaction analysis demonstrated that Stat is a potential key gene influenced by non-obese T2DM.ConclusionsNon-obese T2DM alters cardiac gene expression profile. The altered genes may be involved in the development of cardiac pathologies and could be potential therapeutic targets in non-obese T2DM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0424-3) contains supplementary material, which is available to authorized users.

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RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions

Cited by 14 publications

References 61 publications

RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose

RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose

Acute pulmonary effects of aerosolized nicotine

Transcriptomic alterations in the heart of non-obese type 2 diabetic Goto-Kakizaki rats

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