Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice
Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice
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DOI：
10.1073/pnas.120055097
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发表时间：
2000-07-05
影响因子：
11.1
通讯作者：
Sharma, K
中科院分区：
文献类型：
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作者：
Ziyadeh, FN;Hoffman, BB;Sharma, K
新出现的证据表明，转化生长因子- β (tgf - β)是糖尿病肾病的重要介质。我们之前的研究表明，在链脲佐菌素糖尿病小鼠中，用中和性单克隆抗tgf - β抗体（α T）短期治疗可以防止肾脏肥大的早期改变和基质mRNA的增加。为了证实肾脏tgf - β系统的过度活跃介导了晚期肾病的功能和结构变化，我们在db/db小鼠（一种发展为显性肾病的2型糖尿病模型）中测试了慢性给药α T是否能预防肾功能不全和肾小球硬化。将糖尿病db/db小鼠和非糖尿病db/m窝鼠分别腹腔注射α - T或对照IgG，每次300 μ g，每周3次，连续8周，α - T治疗而不注射IgG治疗可显著降低血浆tgf - β 1浓度，但不降低血浆葡萄糖浓度。igg处理的db/db小鼠出现蛋白尿、肾功能不全和肾小球系膜基质扩张，与编码α 1（IV）胶原和纤维连接蛋白的肾脏mrna增加有关。另一方面，α T治疗完全阻止了db/db小鼠血浆肌酐浓度的增加、尿肌酐清除率的降低和系膜基质的扩张。肾基质mrna的增加明显减弱，但用于肌酐清除率的尿白蛋白因子的排泄没有受到α - T治疗的显著影响。我们得出结论，在db/db小鼠中，用中和性单克隆抗体慢性抑制tgf - β的生物作用可以预防2型糖尿病引起的肾小球硬化和肾功能不全。
Emerging evidence suggests that transforming growth factor-beta (TGF-beta) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-beta antibody (alpha T) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-beta system mediates the functional and structural changes of the more advanced stages of nephropathy, we tested whether chronic administration of alpha T prevents renal insufficiency and glomerulosclerosis in the db/db mouse, a model of type 2 diabetes that develops overt nephropathy. Diabetic db/db mice and nondiabetic db/m littermates were treated intraperitoneally with alpha T or control IgG, 300 mu g three times per week for 8 wk, Treatment with alpha T, but not with IgG, significantly decreased the plasma TGF-beta 1 concentration without decreasing the plasma glucose concentration. The IgG-treated db/db mice developed albuminuria, renal insufficiency, and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding alpha 1(IV) collagen and fibronectin, On the other hand, treatment with alpha T completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factored for creatinine clearance was not significantly affected by alpha T treatment. We conclude that chronic inhibition of the biologic actions of TGF-beta with a neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.