Targeting TGF-β overexpression in renal disease:: Maximizing the antifibrotic action of angiotensin II blockade
Targeting TGF-β overexpression in renal disease:: Maximizing the antifibrotic action of angiotensin II blockade
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DOI：
10.1046/j.1523-1755.1998.00164.x
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发表时间：
1998-11-01
影响因子：
19.6
通讯作者：
Noble, NA
中科院分区：
文献类型：
--
作者：
Peters, H;Border, WA;Noble, NA
背景。转化生长因子- β (tgf - β)的过度产生是纤维化疾病中细胞外基质积累的关键介质。我们假设病理性tgf - β表达的降低程度可以作为肾脏疾病中血管紧张素II （Ang II）阻断的抗纤维化潜力的新指标。在Thy 1.1型肾小球肾炎诱导后1天，在饮用水中增加剂量的Ang I转换酶（ACE）抑制剂依那普利和/或Ang II受体阻滞剂氯沙坦。在疾病诱导后6天观察对肾小球tgf - β过表达的治疗效果。依那普利和氯沙坦都以剂量依赖的方式减少tgf - β的过量产生，在已知的控制肾型高血压血压的剂量下显示出适度的减少。在100mg /l依那普利和500mg /l氯沙坦剂量组中，tgf - β表达的最大降幅约为45%，当依那普利剂量达到1000mg /l或氯沙坦剂量达到2500mg /l时，tgf - β表达没有进一步降低。两种药物联合治疗并不优于单一治疗。与我们的假设一致，减少TGF-P的表达是一个有效的靶标，其他疾病指标，包括肾小球基质积累、肾小球生成、基质蛋白纤维连接蛋白mRNA表达和蛋白酶抑制剂纤溶酶原激活物抑制剂1型（PAI-1）密切关注tgf - β的表达。数据表明，这些疗法通过非常相似的途径起作用，为了更有效地治疗肾纤维化，这些药物必须与其他作用机制不同的药物联合使用。
Background. 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.Methods. 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.Results. 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. Go-treatment with both drugs was not superior to single therapy. Consistent with our hypothesis that reduction in TGF-P 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.Conclusions. 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.