抑制白蛋白糖化可改善db/db小鼠的糖尿病肾病。

M P Cohen, N Masson, E Hud, F Ziyadeh, D C Han, R S Clements
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引用次数: 39

摘要

Amadori葡萄糖加合物修饰的白蛋白刺激肾小球系膜细胞和内皮细胞细胞外基质蛋白的表达,并与糖尿病肾病的发病机制有关。为了验证抑制糖化白蛋白的形成可能有利于糖尿病肾脏疾病发展的假设,我们用一种低分子量化合物(EXO-226)治疗糖尿病db/db小鼠12周,这种化合物可以阻止白蛋白中游离葡萄糖与赖氨酸ε -氨基的冷凝。EXO-226 (3mg /kg)每天两次灌胃,在治疗开始后几天内使血浆糖化白蛋白浓度正常化,并在整个研究期间将糖化白蛋白维持在正常范围内,尽管存在持续和严重的高血糖。尿白蛋白排泄在研究开始时(12周龄)明显增加,与未治疗的糖尿病鼠相比,治疗后的糖尿病鼠尿白蛋白排泄明显减少。在未治疗的糖尿病动物中观察到的肌酐清除率的下降在接受治疗的糖尿病幼崽中得到了预防。与非糖尿病对照组相比,未经治疗的糖尿病小鼠肾小球系膜基质的数量增加了三倍;而系膜基质分数仅为1。治疗后的糖尿病动物是非糖尿病对照组的5倍,表明系膜基质积累减少了50%以上。EXO-226还降低了db/db小鼠肾皮质α 1 (IV)胶原编码mRNA的过表达。我们得出结论,糖基化抑制剂EXO-226使血浆糖化白蛋白浓度正常化,可改善db/db小鼠与糖尿病肾病相关的肾小球结构和功能异常。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibiting albumin glycation ameliorates diabetic nephropathy in the db/db mouse.

Albumin modified by Amadori glucose adducts stimulates the expression of extracellular matrix proteins by glomerular mesangial and endothelial cells, and has been mechanistically linked to the pathogenesis of diabetic nephropathy. To test the hypothesis that inhibiting the formation of glycated albumin might beneficially influence the development of kidney disease in diabetes, we treated diabetic db/db mice for 12 weeks with a low-molecular-weight compound (EXO-226) that impedes the condensation of free glucose with lysine epsilon-amino groups in albumin. Administration of EXO-226 (3 mg/kg) twice daily by gavage normalized the plasma concentration of glycated albumin within days after initiation of treatment and maintained glycated albumin within the normal range throughout the study, despite persistent and severe hyperglycemia. Urine albumin excretion, which was markedly increased at the start of the study (age 12 weeks), was significantly reduced in treated diabetic animals compared with their untreated diabetic littermates. The fall in creatinine clearance that was observed in untreated diabetic animals was prevented in diabetic littermates that received treatment. Compared with the nondiabetic controls, the amount of glomerular mesangial matrix was threefold greater in untreated diabetic mice; in contrast, the mesangial matrix fraction was only 1. 5 times that of nondiabetic controls in the treated diabetic animals, representing a reduction in mesangial matrix accumulation of more than 50%. EXO-226 also reduced the overexpression of mRNA encoding for alpha1 (IV) collagen in renal cortex of db/db mice. We conclude that normalization of plasma glycated albumin concentrations with the glycation inhibitor EXO-226 ameliorates the glomerular structural and functional abnormalities associated with diabetic nephropathy in the db/db mouse.

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