J Clin Neurol.  2014 Oct;10(4):334-341. 10.3988/jcn.2014.10.4.334.

Up-Regulation of the Receptor for Advanced Glycation End Products in the Skin Biopsy Specimens of Patients with Severe Diabetic Neuropathy

• Park SY
• Kim YA
• Hong YH
• Moon MK
• Koo BK
• Kim TW

• KMID: 2287513
• DOI: http://doi.org/10.3988/jcn.2014.10.4.334

Abstract

BACKGROUND AND PURPOSE
The receptor for advanced glycation end products (RAGE) may contribute to the development of diabetic neuropathy. To assess its relevance in humans, this study examined the expression of RAGE in the skin biopsy samples of patients with diabetes mellitus, and investigated its correlation with intraepidermal nerve-fiber density (IENFD) and clinical measures of neuropathy severity.
METHODS
Forty-four patients who either had type 2 diabetes or were prediabetes underwent clinical evaluation and a 3-mm skin punch biopsy. The clinical severity of their neuropathy was assessed using the Michigan Diabetic Neuropathy Score. IENFD was measured along with immunohistochemical staining for RAGE in 29 skin biopsy samples. The expression of RAGE was 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 of RAGE mRNA was significantly higher in patients with severe neuropathy than in those with no or 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 amplitude and slowed peroneal motor-nerve conduction with increasing RAGE expression.
CONCLUSIONS
The findings of this study demonstrate up-regulation of RAGE in skin biopsy samples from patients with diabetic neuropathy, supporting a pathogenic role of RAGE in the development of diabetic neuropathy.

Keyword

receptor for advanced glycation end products; diabetes mellitus; diabetic neuropathy

MeSH Terms

Biopsy*
Diabetes Mellitus
Diabetic Nephropathies
Diabetic Neuropathies*
Dyslipidemias
Glycosylation End Products, Advanced*
Humans
Michigan
Polymerase Chain Reaction
Prediabetic State
Rage
RNA, Messenger
Skin*
Sural Nerve
Up-Regulation*
Advanced Glycosylation End Product-Specific Receptor
Glycosylation End Products, Advanced
RNA, Messenger

Figure

• 

  Fig. 1 Intraepidermal nerve-fiber density (IENFD) in skin biopsy specimens of patients with different clinical severities of diabetic neuropathy. A: Kruskal-Wallis rank sum test, p=0.00017. B: Spearman correlation analysis, rho=-0.76, p<0.0001.

• 

  Fig. 2 Immunohistochemical staining (×200) for receptor for advanced glycation end products (RAGE) in the vascular endothelium (arrowheads) of the superficial dermis (A), deep dermis (B), and subcutaneous region (C) in a patient with severe diabetic neuropathy. Basal cells in the epidermis are marginally stained for RAGE, although it is difficult to distinguish between the melatonin in those cells and the immunoreactivity (A).

• 

  Fig. 3 Intraepidermal nerve-fiber density (IENFD) in skin biopsy specimens of patients with different levels of immunostaining for receptor for advanced glycation end products (RAGE); Kruskal-Wallis rank sum test, p=0.0037 (A). Relative change in RAGE mRNA (relative to glyceraldehyde 3-phosphate dehydrogenase), normalized to the expression in the lung (calibrator tissue), as quantified by real-time reverse-transcription PCR (B). Each bar represents the result for an individual patient. The mean and upper (lower) errors were determined from triplicates of each sample. Wilcoxon rank sum test for comparison of severe vs. no or mild neuropathy, p=0.0028.

• 

  Fig. 4 Relationships between receptor for advanced glycation end products (RAGE) expression and nerve-conduction parameters. Sural sensory-nerve action potential (SNAP) amplitudes (A and B), and peroneal motor-nerve conduction velocities (MNCVs) (C and D). RAGE immunohistochemical staining (A and C), and RAGE reverse-transcription-PCR (B and D).

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