Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy.
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.


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.
Toth
Cory
C
University of Calgary, Department of Clinical Neurosciences, Room 155, 3330 Hospital Dr., N.W., Calgary, Alberta T2N 4N1, Canada. corytoth@shaw.ca
Rong
Ling Ling
LL
Yang
Christina
C
Martinez
Jose
J
Song
Fei
F
Ramji
Noor
N
Brussee
Valentine
V
Liu
Wei
W
Durand
Jeff
J
Nguyen
Minh Dang
MD
Schmidt
Ann Marie
AM
Zochodne
Douglas W
DW
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000097:blood / Q000503:physiopathology*; D018450:Disease Progression; D005727:Ganglia, Spinal / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009431:Neural Conduction; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism*; D012584:Sciatic Nerve / Q000503:physiopathology*
D001786:Blood Glucose; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic