RAGE and Experimental Diabetic Neuropathy

Abstract

Background: 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.

Objective: We studied experimental diabetic neuropathy and its relationship with RAGE expression using streptozotocin (STZ) diabetic mice including a RAGE^-/- cohort exposed to long-term diabetes, as compared to littermates without diabetes.

Methods: Structural indices 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 wildtype and RAGE^-/- mice, with and without diabetes. The correlation of RAGE activation with nuclear factor κB (NFκB) 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 NFκB and PKCβII pathways was most evident amongst Schwann cells in the DRG and peripheral nerve.

Conclusion: 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.