Up-Regulation of the Receptor for Advanced Glycation End Products in the Skin Biopsy Specimens of Patients with Severe Diabetic Neuropathy
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Background and Purpose The receptor for advanced glycation end products (RAGE) maycontribute to the development of diabetic neuropathy. To assess its relevance in humans, thisstudy examined the expression of RAGE in the skin biopsy samples of patients with diabetesmellitus, and investigated its correlation with intraepidermal nerve-fiber density (IENFD) andclinical measures of neuropathy severity. Methods Forty-four patients who either had type 2 diabetes or were prediabetes underwentclinical evaluation and a 3-mm skin punch biopsy. The clinical severity of their neuropathy wasassessed using the Michigan Diabetic Neuropathy Score. IENFD was measured along with immunohistochemical staining for RAGE in 29 skin biopsy samples. The expression of RAGEwas also quantified by real-time reverse-transcription PCR in the remaining 15 patients. Results RAGE was localized mostly in the dermal and subcutaneous vascular endothelia. The staining was more intense in patients with a lower IENFD (p=0.004). The quantity ofRAGE mRNA was significantly higher in patients with severe neuropathy than in those with noor mild neuropathy (p=0.003). The up-regulation of RAGE was related to dyslipidemia and diabetic nephropathy. There was a trend toward decreased sural nerve action-potential amplitudeand slowed peroneal motor-nerve conduction with increasing RAGE expression. Conclusions The findings of this study demonstrate up-regulation of RAGE in skin biopsysamples from patients with diabetic neuropathy, supporting a pathogenic role of RAGE in thedevelopment of diabetic neuropathy.
Abstract
Background and Purpose The receptor for advanced glycation end products (RAGE) maycontribute to the development of diabetic neuropathy. To assess its relevance in humans, thisstudy examined the expression of RAGE in the skin biopsy samples of patients with diabetesmellitus, and investigated its correlation with intraepidermal nerve-fiber density (IENFD) andclinical measures of neuropathy severity. Methods Forty-four patients who either had type 2 diabetes or were prediabetes underwentclinical evaluation and a 3-mm skin punch biopsy. The clinical severity of their neuropathy wasassessed using the Michigan Diabetic Neuropathy Score. IENFD was measured along with immunohistochemical staining for RAGE in 29 skin biopsy samples. The expression of RAGEwas also quantified by real-time reverse-transcription PCR in the remaining 15 patients. Results RAGE was localized mostly in the dermal and subcutaneous vascular endothelia. The staining was more intense in patients with a lower IENFD (p=0.004). The quantity ofRAGE mRNA was significantly higher in patients with severe neuropathy than in those with noor mild neuropathy (p=0.003). The up-regulation of RAGE was related to dyslipidemia and diabetic nephropathy. There was a trend toward decreased sural nerve action-potential amplitudeand slowed peroneal motor-nerve conduction with increasing RAGE expression. Conclusions The findings of this study demonstrate up-regulation of RAGE in skin biopsysamples from patients with diabetic neuropathy, supporting a pathogenic role of RAGE in thedevelopment of diabetic neuropathy.
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