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Suppression of nNOS expression in rat enteric neurones by the receptor for advanced glycation end-products

Authors

  • K. Korenaga,

    1. Enteric Neuromuscular Disorders and Pain Group, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
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  • M.-a. Micci,

    1. Enteric Neuromuscular Disorders and Pain Group, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
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  • G. Taglialatela,

    1. Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA
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  • P. J. Pasricha

    1. Enteric Neuromuscular Disorders and Pain Group, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
    2. Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA
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P. Jay Pasricha MD, Chief, Division of Gastroenterology and Hepatology, Frances and Bassel Distinguished Professor of Medicine, University of Texas Medical Branch, 4.106 McCullough Building, 301 University Boulevard, Galveston, TX 77555-0764, USA.
Tel: 409 772 5615; fax: 409 772 4789;
e-mail: jpasrich@utmb.edu

Abstract

Abstract  Diabetes mellitus results in a loss of neuronal nitric oxide synthase (nNOS) expression in the myenteric plexus but the underlying mechanisms remain unknown. We hypothesized that this may be mediated by advanced glycation end-products (AGEs), a class of modified protein adducts formed by non-enzymatic glycation that interact with the receptor for AGE (RAGE) and which are important in the pathogenesis of other diabetic complications. Whole mount preparations of longitudinal muscles with adherent myenteric plexus (LM-MPs) from the duodenum of adult male rats were exposed to glycated bovines serum albumin (AGE-BSA) or BSA for 24 h. Western blotting, immunohistochemistry and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for mRNA showed a significant reduction in nNOS expression in LM-MPs after exposure to AGE-BSA. NO release, as measured by the Griess reaction, was also significantly reduced by AGE-BSA. A neutralizing antibody against RAGE attenuated the reduction of nNOS protein caused by AGE-BSA. Immunohistochemistry revealed co-localization of RAGE expression with Hu, a marker for neuronal cells but not for S-100, a glial marker. Advanced glycation end-products reduce nNOS expression in the rat myenteric neurones acting via the receptor RAGE. Our results suggest novel pathways for disruption of the nitrergic phenotype in diabetes.

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