Jin Heung Yong, Piao Ming Han, Park Ji Hyun, Baek Hong Sun, Lee Sik, Kim Won, Park Sung Kwang, Kim Chong Hwa, Koh Gou Young, Park Tae Sun
Endocrinology and Metabolism and Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, South Korea.
Renal Regeneration Laboratory and Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, South Korea.
Curr Ther Res Clin Exp. 2008 Aug;69(4):343-55. doi: 10.1016/j.curtheres.2008.08.002.
Vascular and inflammatory processes have been reported to be factors in the pathogenesis of diabetic neuropathy. Angiopoietin-1 (Ang1) plays essential roles in regulating vascular growth, development, maturation, permeability, and inflammation.
The aim of this study was to investigate the effect of cartilage oligomeric matrix protein (COMP)-Ang1, which is a soluble, stable, potent Ang1 variant, on peripheral nerves in db/db diabetic mice.
The db/db diabetic mice were randomized into 2 groups based on their weight and glucose level and treated with recombinant adenovirus (Ade), expressing either COMP-Ang1 or the β-galactosidase gene (LacZ) (control), for 8 weeks. Immunohistochemistry was performed using a polyclonal antibody of antiprotein gene product and a secondary antibody. Intraepidermal nerve fiber density (IENFD) was quantified as nerve fiber abundance per unit length of epidermis (IENF/mm). In addition, the total capillary length (TCL) per unit length of epidermis was summed (mm/mm(2)). All slides were coded and the capillary length and the number of nerve fibers were calculated by a blinded observer.
Ten diabetic db/db mice (mean [SD] weight, 38.7 [1.95] g) were randomized to receive Ade-COMP-Ang1 or Ade-LacZ. IENFD was significantly greater in the Ade-COMP-Ang1 group compared with the Ade-LacZ group (mean [SD] 8.95 [3.30] vs 3.57 [0.73]/mm; P < 0.05). TCL was also significantly greater in the Ade-COMP-Ang1 group (2.79 [0.99] vs 2.04 [0.58] mm/mm(2); P < 0.05). Compared with baseline, fasting blood glucose concentration after 8 weeks of treatment decreased significantly more in the Ade-COMP-Ang1 group than in the Ade-LacZ group (489 [45] to 361 [81] vs 495 [48] to 521 [70] mg/dL; P < 0.05).
These results suggest that Ade-COMP-Ang1 might have had proliferative effects on peripheral nerve and cutaneous capillaries in this small animal study. Further investigation of the metabolic effect, target site, and related mediator of COMP-Ang1 is needed.
血管和炎症过程据报道是糖尿病性神经病变发病机制中的因素。血管生成素-1（Ang1）在调节血管生长、发育、成熟、通透性和炎症方面发挥着重要作用。
本研究旨在探讨软骨寡聚基质蛋白（COMP）-Ang1（一种可溶性、稳定且强效的Ang1变体）对db/db糖尿病小鼠外周神经的影响。
将db/db糖尿病小鼠根据体重和血糖水平随机分为2组，并用表达COMP-Ang1或β-半乳糖苷酶基因（LacZ）（对照）的重组腺病毒（Ade）治疗8周。使用抗蛋白基因产物的多克隆抗体和二抗进行免疫组织化学。表皮内神经纤维密度（IENFD）被量化为每单位表皮长度的神经纤维丰度（IENF/mm）。此外，将每单位表皮长度的总毛细血管长度（TCL）相加（mm/mm²）。所有切片均进行编码，毛细血管长度和神经纤维数量由一位不知情的观察者计算。
10只糖尿病db/db小鼠（平均[标准差]体重，38.7[1.95]g）被随机分配接受Ade-COMP-Ang1或Ade-LacZ。与Ade-LacZ组相比，Ade-COMP-Ang1组的IENFD显著更高（平均[标准差]8.95[3.30]对3.57[0.73]/mm；P<0.05）。Ade-COMP-Ang1组的TCL也显著更高（2.79[0.99]对2.04[0.58]mm/mm²；P<0.05）。与基线相比，治疗8周后Ade-COMP-Ang1组的空腹血糖浓度下降幅度明显大于Ade-LacZ组（489[45]至361[81]对495[48]至521[70]mg/dL；P<0.05）。
这些结果表明，在这项小动物研究中，Ade-COMP-Ang1可能对外周神经和皮肤毛细血管具有增殖作用。需要进一步研究COMP-Ang1的代谢作用、靶位点和相关介质。
