Mycophenolate mofetil slows progression in anti-thy1-induced chronic renal fibrosis but is not additive to a high dose of enalapril
Mycophenolate mofetil slows progression in anti-thy1-induced chronic renal fibrosis but is not additive to a high dose of enalapril
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DOI：
10.1152/ajprenal.00442.2004
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发表时间：
2005-08-01
影响因子：
4.2
通讯作者：
Peters, H
中科院分区：
文献类型：
--
作者：
Krämer, S;Loof, T;Peters, H
肾小管间质炎症和纤维化是慢性进行性肾病的标志。为了表征细胞浸润和基质扩张之间的功能相互作用，本研究比较了免疫抑制剂吗替麦考酚酯（MMF）（主要用作抗炎干预）、血管紧张素转换酶抑制剂依那普利（主要用作抗纤维化药物）以及两者的组合（预期用作抗炎/抗纤维化干预）。使用的模型是抗 thy1 诱导的大鼠慢性进行性肾小球硬化症 (cGS)，其中短暂的抗 thy1 诱导的肾小球损伤自发进展为肾小管间质纤维化和肾功能不全。通过将抗 thy1 抗体注射到未切除肾的 Wistar 大鼠中来诱导 cGS。疾病诱导一周后，动物被随机分配到以下组：cGS、cGS加MMF（20mg（.）kg体重（-1.）天（-1））、cGS加高剂量依那普利（12mg（.）kg体重（-1.）天（-1））和cGS加两者。在疾病诱导后第 16 周，与未治疗的 cGS 组相比，单独使用 MMF 或依那普利可显着且相似地减少慢性肾病的体征。测量的变量包括蛋白尿、血压、肾小管间质和肾小球基质积累、转化生长因子-β(1)、纤连蛋白和纤溶酶原激活剂抑制剂-1的表达、淋巴细胞和巨噬细胞的浸润、血浆肌酐和尿素水平以及肾小球滤过率。 MMF 和依那普利联合治疗并不优于单一治疗。总之，在抗 thy1 诱导的慢性进行性肾小球硬化模型中，MMF 与高剂量依那普利一样有效地减缓慢性肾纤维化和肾功能不全的进展。双重抗炎/抗纤维化干预不会产生额外的肾脏保护作用，表明 MMF 和依那普利干扰参与肾脏疾病进展的相似或非常密切相关的途径。
Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg(.)kg body wt(-1.)day(-1)), cGS plus high- dose enalapril (12 mg(.)kg body wt(-1.)day(-1)), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-beta(1), fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high- dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease.