Peters H, Border W A, Noble N A
Division of Nephrology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Kidney Int. 1998 Nov;54(5):1570-80. doi: 10.1046/j.1523-1755.1998.00164.x.
Overproduction of transforming growth factor-beta (TGF-beta) is a key mediator of extracellular matrix accumulation in fibrotic diseases. We hypothesized that the degree of reduction of pathological TGF-beta expression can be used as a novel index of the antifibrotic potential of angiotensin II (Ang II) blockade in renal disease.
One day after induction of Thy 1.1 glomerulonephritis, rats were treated with increasing doses of the Ang I converting enzyme (ACE) inhibitor enalapril and/or the Ang II receptor blocker losartan in the drinking water. Six days after disease induction the therapeutic effect on glomerular TGF-beta overexpression was evaluated.
Both enalapril and losartan reduced TGF-beta overproduction in a dose-dependent manner, showing a moderate reduction at doses known to control blood pressure in renal forms of hypertension. A maximal reduction in TGF-beta expression of approximately 45% was seen for both drugs starting at 100 mg/liter enalapril and 500 mg/liter losartan, with no further reduction at doses of enalapril up to 1000 mg/liter or losartan up to 2500 mg/liter. Co-treatment with both drugs was not superior to single therapy. Consistent with our hypothesis that reduction in TGF-beta expression is a valid target, other disease measures, including glomerular matrix accumulation, glomerular production and mRNA expression of the matrix protein fibronectin and the protease inhibitor plasminogen-activator-inhibitor type 1 (PAI-1) closely followed TGF-beta expression.
The data suggest that these therapies act through very similar pathways and that, in order to more effectively treat renal fibrosis, these drugs must be combined with other drugs that act by different mechanisms.
转化生长因子-β（TGF-β）过度产生是纤维化疾病中细胞外基质积聚的关键介质。我们假设病理性TGF-β表达的降低程度可作为评估血管紧张素II（Ang II）阻断治疗肾脏疾病抗纤维化潜力的新指标。
在诱导Thy 1.1肾小球肾炎一天后，给大鼠饮用含递增剂量血管紧张素I转换酶（ACE）抑制剂依那普利和/或血管紧张素II受体阻滞剂氯沙坦的水。疾病诱导六天后，评估对肾小球TGF-β过表达的治疗效果。
依那普利和氯沙坦均以剂量依赖性方式降低TGF-β的过度产生，在已知可控制肾性高血压血压的剂量下显示出适度降低。从依那普利100 mg/升和氯沙坦500 mg/升开始，两种药物对TGF-β表达的最大降低约为45%，依那普利剂量高达1000 mg/升或氯沙坦剂量高达2500 mg/升时无进一步降低。两种药物联合治疗并不优于单一治疗。与我们关于TGF-β表达降低是有效靶点的假设一致，其他疾病指标，包括肾小球基质积聚、基质蛋白纤连蛋白的肾小球产生和mRNA表达以及蛋白酶抑制剂纤溶酶原激活物抑制剂1型（PAI-1）密切跟随TGF-β表达。
数据表明这些疗法通过非常相似的途径起作用，并且为了更有效地治疗肾纤维化，这些药物必须与通过不同机制起作用的其他药物联合使用。
