Angiotensin-converting enzyme inhibition but not β-adrenergic blockade limits transforming growth factor-β overexpression in acute normotensive anti-thy1 glomerulonephritis
Angiotensin-converting enzyme inhibition but not β-adrenergic blockade limits transforming growth factor-β overexpression in acute normotensive anti-thy1 glomerulonephritis
复制标题
血管紧张素转换酶抑制而非β-肾上腺素能阻断限制了急性正常血压抗 thy1 肾小球肾炎中转化生长因子-β 的过度表达
作者：
H. Peters;Matthias Rückert;J. Gaedeke;L. Liefeldt;M. Ketteler;Arya M. Sharma;H. Neumayer
目的近年来慢性肾脏病的实验研究表明，交感神经阻滞剂，类似于血管紧张素II拮抗剂，限制肾纤维化不依赖于血压控制。使用急性和血压正常的抗-thy 1肾小球肾炎模型，我们分析了β-肾上腺素能阻断（与血管紧张素转换酶抑制相比）对促纤维化细胞因子转化生长因子（TGF）-β在肾脏过度表达的作用。方法在建立抗Thy 1抗体肾炎模型后1d，分别以已知血压剂量的0.1倍、1倍、10倍和20倍剂量给予β受体阻滞剂美托洛尔或奈必洛尔，直至第6天，20倍剂量给予至第12天。其他动物用高剂量的血管紧张素转化酶抑制剂依那普利治疗。实验结束时记录血压和心率，对肾小球基质扩张进行组织学评分，并检测培养肾小球上清液中TGF-β1、纤连蛋白和纤溶酶原激活物抑制剂-1的蛋白表达。结果美托洛尔和奈必洛尔均呈剂量依赖性降低心率。未给药动物的血压正常，未受任何给药的显著影响。与未治疗的肾炎大鼠相比，美托洛尔或奈必洛尔在任何剂量或治疗期间均未显著改变TGF-β1的过度表达。相反，在疾病诱导后6天和12天，依那普利显著降低TGF-β1水平（分别为-52%和-63%）。肾小球基质评分、纤连蛋白和纤溶酶原激活物抑制剂-1的产生变化与TGF-β1的表达密切相关。结论在正常血压的急性肾小球纤维化模型中，β-肾上腺素能拮抗剂不能减少TGF-β的过度表达，提示其压力非依赖性抗纤维化作用可能仅限于慢性肾脏疾病。血管紧张素II抑制的有益作用，甚至对急性基质扩张可能是一个相关的机制，以解释其在治疗纤维化肾病的优势。
Objective Recent experimental studies in chronic kidney disease have suggested that sympathicolytic drugs, similar to angiotensin II antagonism, limit renal fibrosis independent of blood pressure control. Using the model of acute and normotensive anti-thy1 glomerulonephritis, we analysed the action of β-adrenergic blockade (as compared with angiotensin-converting enzyme inhibition) on renal overexpression of the profibrotic cytokine transforming growth factor (TGF)-β. Methods One day after induction of anti-thy1 glomerulonephritis, rats were given increasing doses of the β-blockers metoprolol or nebivolol (0.1-fold, one-fold, 10-fold and 20-fold of the known blood pressure dose) until day 6 and the 20-fold dose until day 12. Additional animals were treated with a high dose of the angiotensin-converting enzyme inhibitor enalapril. At the end of each experiment, blood pressure and heart rate were recorded, glomerular matrix expansion was scored histologically, and protein expression of TGF-β1, fibronectin and plasminogen activator inhibitor-1 was determined in the supernatant of cultured glomeruli. Results Metoprolol and nebivolol reduced heart rate in a dose-dependent manner. Blood pressure was normal in untreated animals and not significantly affected by either treatment. Compared with untreated nephritic rats, TGF-β1 overexpression was not significantly changed by metoprolol or nebivolol in any dose or treatment period. In contrast, TGF-β1 levels were significantly reduced by enalapril both 6 and 12 days after disease induction (–52 and –63%, respectively). The changes in glomerular matrix score, fibronectin and plasminogen activator inhibitor-1 production closely followed expression of TGF-β1. Conclusions In a model of acute and normotensive glomerular fibrosis, β-adrenergic antagonism does not reduce TGF-β overexpression, suggesting that its pressure-independent antifibrotic action may be limited to chronic renal diseases. The beneficial effect of angiotensin II inhibition even on acute matrix expansion may be a relevant mechanism as to the explanation of its superiority in treating fibrotic renal diseases.
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DOI：
10.1073/pnas.120055097
发表时间：
2000-07-05
影响因子：
11.1
作者：
Ziyadeh, FN;Hoffman, BB;Sharma, K
通讯作者：
Sharma, K
影响因子：
9.3
作者：
R. Magnotti;G. Stephens;R. K. Rogers;A. Pesce
通讯作者：
R. Magnotti;G. Stephens;R. K. Rogers;A. Pesce
DOI：
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发表时间：
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期刊：
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影响因子：
--
作者：
通讯作者：
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影响因子：
19.6
作者：
Peters, H;Border, WA;Noble, NA
通讯作者：
Noble, NA
影响因子：
13.2
作者：
CAMPESE, VM;KOGOSOV, E;KOSS, M
通讯作者：
KOSS, M