HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db07-0339v1 57/4/1002    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Toth, C. Articles by Zochodne, D. W. Search for Related Content PubMed PubMed Citation Articles by Toth, C. Articles by Zochodne, D. W. Social Bookmarking                What's this?

Receptor for Advanced Glycation End Products (RAGEs) and Experimental Diabetic Neuropathy

¹ Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
² Department of Surgery, Columbia University, New York, New York

Address correspondence and reprint requests to Dr. C. Toth, University of Calgary, Department of Clinical Neurosciences, Room 155, 3330 Hospital Dr., N.W., Calgary, Alberta T2N 4N1, Canada. E-mail: corytoth{at}shaw.ca

Abbreviations: AGE, advanced glycation end product; CML, NH₂-(carboxymethyl)lysine; DRG, dorsal root ganglia; NF, nuclear factor; PBT, PBS with 0.1% Tween-20; PKC, protein kinase C; PNS, peripheral nervous system; RAGE, receptor for AGEs; STZ, streptozotocin

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)-B and protein kinase C βII (PKCβII) 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-B and PKCβII 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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				V. Brussee, G. Guo, Y. Dong, C. Cheng, J. A. Martinez, D. Smith, G. W. Glazner, P. Fernyhough, and D. W. Zochodne Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model Diabetes, June 1, 2008; 57(6): 1664 - 1673. [Abstract] [Full Text] [PDF]