PREVENTION OF DIABETIC NEPHROPATHY IN DB/DB MICE WITH GLYCATED ALBUMIN ANTAGONISTS - A NOVEL TREATMENT STRATEGY
PREVENTION OF DIABETIC NEPHROPATHY IN DB/DB MICE WITH GLYCATED ALBUMIN ANTAGONISTS - A NOVEL TREATMENT STRATEGY
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DOI：
10.1172/jci117926
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发表时间：
1995-05-01
影响因子：
15.9
通讯作者：
ZIYADEH, FN
中科院分区：
文献类型：
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作者：
COHEN, MP;SHARMA, K;ZIYADEH, FN
糖尿病中蛋白质糖化加速与糖尿病肾病的发病机制有关。由于糖化白蛋白可诱导培养的系膜细胞出现类似糖尿病肾小球系膜细胞的异常，而针对Amadori修饰的糖化白蛋白的单抗(A717)可阻止这些异常，我们推测体内注射A717可以延缓糖尿病肾病的进展，为了验证这一假设，糖尿病db/db小鼠及其非糖尿病db/m仔鼠每周连续8次注射A717(Fab片段)以降低升高的血浆糖化白蛋白浓度，或与非糖尿病患者无关的小鼠免疫球蛋白(MiG)。糖尿病小鼠(MiG治疗组)出现蛋白尿(3.35+/-0.15vs0.87+/-0.1 mg白蛋白/mg肌酐)，系膜基质成分增加3.8倍，肾皮质编码α1(IV)胶原的mRNAs(2.6倍增加)和纤维连接蛋白(3.8倍增加)，A717治疗db/db小鼠显著减少蛋白尿(1.52+/-0.3 mg/mg肌酐)，抑制系膜基质扩张，减弱基质mRNAs的过度表达，A717的肾脏保护作用不依赖于血糖浓度的任何变化。不与糖化白蛋白反应的抗体不能复制A717的有益作用，因此，用A717消除糖化白蛋白增加的生物学作用在糖尿病肾病的发病机制中具有有益的影响，并在其治疗方面具有新的治疗潜力。
Accelerated protein glycation in diabetes has been mechanistically linked to the pathogenesis of diabetic nephropathy. Because glycated albumin induces abnormalities in cultured mesangial cells that resemble those characterizing the glomerular mesangium in diabetes, and monoclonal antibodies (A717) specific for Amadori-modified glycated albumin prevent these abnormalities, we postulated that in vivo administration of A717 could retard the progression of diabetic nephropathy, To test this hypothesis, diabetic db/db mice and their nondiabetic db/m littermates were treated with eight consecutive weekly injections of 150 mu g of A717 (Fab fragments) to reduce the elevated plasma glycated albumin concentration, or with irrelevant murine IgG (MIg), Relative to nondiabetics, diabetic mice (MIg treated) manifested proteinuria (3.35+/-0.15 vs 0.87+/-0.1 mg albumin/mg creatinine), 3.8-fold increase in mesangial matrix fraction, and renal cortical overexpression of mRNAs encoding alpha 1(IV) collagen (2.6-fold increase) and fibronectin (3.8-fold increase), Treatment of db/db mice with A717 significantly reduced the proteinuria (1.52+/-0.3 mg/mg creatinine), inhibited mesangial matrix expansion, and attenuated overexpression of matrix mRNAs, The nephropathic protective effects of A717 were independent of any change in blood glucose concentrations, Antibodies unreactive with glycated albumin did not duplicate the beneficial effects of A717, Thus, abrogating the biologic effects of increased glycated albumin with A717 has a salutary influence on the pathogenesis of diabetic nephropathy and has novel therapeutic potential in its management.