Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-Ay/Ta mice
Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-Ay/Ta mice
复制标题
DOI：
10.1016/j.metabol.2006.08.026
复制
发表时间：
2007-02-01
影响因子：
9.8
通讯作者：
Tomino, Yasuhiko
中科院分区：
文献类型：
--
作者：
Tanimoto, Mitsuo;Gohda, Tomohito;Tomino, Yasuhiko
美拉德反应产生的晚期糖基化终产物(AGEs)参与了糖尿病相关并发症的发病机制，如糖尿病肾病。在减少AGEs的治疗干预中，许多化合物被报道为AGE抑制剂。本研究的目的是观察AGE抑制剂吡哆胺(K-163)对2型糖尿病KK-A(Y)/Ta小鼠的影响。KK-A(Y)/Ta小鼠从8周龄开始给予吡哆胺(200或400 mg/kg/d)，连续12周。随机分为吡哆胺200 mg/(kg·d)治疗组(n=10)、吡哆胺400 mg/(kg·d)治疗组(n=10)和自来水对照组(n=20)。以尿白蛋白/肌酐比值(ACR)、体重(BW)、空腹和空腹血糖、糖化血红蛋白(HbA(1c))、空腹血清胰岛素(FINS)、甘油三酯(TG)、总胆固醇(T-CHO)、3-脱氧葡萄糖(3DG)和全身血压为生化指标。免疫组织化学方法检测肾小球内N-表位羧甲基赖氨酸(CML)和硝基酪氨酸的积聚。用实时定量聚合酶链式反应检测肾脏转化生长因子-β1和层粘连蛋白-β1信使RNA的表达。吡哆胺，尤其是400 mg/kg/d，可改善尿ACR、空腹血清甘油三酯和3DG水平。肾小球内慢性粒细胞白血病和硝基酪氨酸蓄积减少。此外，大剂量的吡哆胺不仅可以防止尿ACR，还可以防止体重、随机血糖和糖化血红蛋白(1c)的增加。肾组织中转化生长因子-β1和层粘连蛋白-β1信使RNA的表达显著低于对照组。所有患者的空腹血糖、血清总胆固醇和全身血压水平均无明显变化。在KK-A(Y)/Ta小鼠的肾脏中，吡哆胺似乎通过其抗衰老和抗氧化作用而改善了尿ACR。(C)2007 Elsevier Inc.保留所有权利。
Advanced glycation end products (AGEs) from the Maillard reaction contribute to the pathogenesis of diabetes-associated complications such as diabetic nephropathy. In therapeutic interventions for reducing AGEs, many compounds have been reported as AGE inhibitors. The objective of the present study was to examine the effect of pyridoxamine (K-163), an AGE inhibitor, in type 2 diabetic KK-A(y)/Ta mice. KK-A(y)/Ta mice were given pyridoxamine (200 or 400 mg/kg per day) starting at 8 weeks of age for 12 weeks. They were divided into 3 groups as follows: pyridoxamine 200 mg/kg per day treatment group (n = 10), pyridoxamine 400 mg/kg per day treatment group (n = 10), and a tap water group as the control group (n = 20). The urinary albumin/creatinine ratio (ACR), body weight (BW), levels of fasting and casual blood glucose, blood glycated hemoglobin (HbA(1c)), fasting serum insulin, triglyceride (TG), total cholesterol (T-Cho), and 3-deoxyglucosone (3DG), and systemic blood pressure were measured as biochemical parameters. N-epsilon-(Carboxymethyl)lysine (CML) and nitrotyrosine accumulations in glomeruli were evaluated by immunohistochemical analyses. Transforming growth factor beta 1 (TGF-beta 1) and laminin-beta 1 messenger RNA expressions in the kidneys were evaluated by real-time polymerase chain reaction. Pyridoxamine, especially at 400 mg/kg per day, improved the levels of urinary ACR, fasting serum TG, and 3DG. CML and nitrotyrosine accumulations in glomeruli were decreased. Furthermore, large doses of pyridoxamine prevented not only urinary ACR but also increases of BW, casual blood glucose, and HbA(1c). TGF-beta 1 and laminin-beta 1 messenger RNA expressions in kidneys were significantly lower than those in the controls. There were no significant changes in the levels of fasting blood glucose, serum T-Cho, and systemic blood pressure among all groups. It appears that pyridoxamine improved urinary ACR by its anti-AGE and anti-oxidant effects in the kidneys of KK-A(y)/Ta mice. (c) 2007 Elsevier Inc. All rights reserved.