Department of Neurology, Korea Cancer Center Hospital, Seoul, Korea.
Department of Pathology, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
J Clin Neurol. 2014 Oct;10(4):334-41. doi: 10.3988/jcn.2014.10.4.334. Epub 2014 Oct 6.
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.
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.
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.
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.
晚期糖基化终产物受体（RAGE）可能有助于糖尿病性神经病的发展。为了评估其在人类中的相关性，本研究检测了糖尿病患者皮肤活检样本中 RAGE 的表达，并研究了其与表皮内神经纤维密度（IENFD）和神经病严重程度的临床指标的相关性。
44 例患者患有 2 型糖尿病或糖尿病前期，接受了临床评估和 3mm 皮肤打孔活检。使用密歇根糖尿病神经病评分评估其神经病的严重程度。在 29 例皮肤活检样本中进行 RAGE 的免疫组织化学染色，同时测量 IENFD。在其余 15 例患者中，还通过实时逆转录 PCR 定量 RAGE 的表达。
RAGE 主要定位于真皮和皮下血管内皮。在 IENFD 较低的患者中，染色更强烈（p=0.004）。严重神经病患者的 RAGE mRNA 数量明显高于无或轻度神经病患者（p=0.003）。RAGE 的上调与血脂异常和糖尿病肾病有关。随着 RAGE 表达的增加，出现腓肠神经动作电位幅度降低和腓总运动神经传导速度减慢的趋势。
本研究发现糖尿病性神经病患者皮肤活检样本中 RAGE 的上调，支持 RAGE 在糖尿病性神经病发展中的致病作用。
