Peters Harm, Rückert Matthias, Gaedeke Jens, Liefeldt Lutz, Ketteler Markus, Sharma Arya M, Neumayer Hans-H
Division of Nephrology, Charité, Campus Mitte, Humboldt-University, Berlin, Germany.
J Hypertens. 2003 Apr;21(4):771-80. doi: 10.1097/00004872-200304000-00021.
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 beta-adrenergic blockade (as compared with angiotensin-converting enzyme inhibition) on renal overexpression of the profibrotic cytokine transforming growth factor (TGF)-beta.
One day after induction of anti-thy1 glomerulonephritis, rats were given increasing doses of the beta-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-beta(1), fibronectin and plasminogen activator inhibitor-1 was determined in the supernatant of cultured glomeruli.
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-beta(1) overexpression was not significantly changed by metoprolol or nebivolol in any dose or treatment period. In contrast, TGF-beta(1) 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-beta(1).
In a model of acute and normotensive glomerular fibrosis, beta-adrenergic antagonism does not reduce TGF-beta 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.
近期针对慢性肾病的实验研究表明，与血管紧张素II拮抗剂类似，交感神经解抗药物可独立于血压控制之外限制肾纤维化。我们利用急性和血压正常的抗thy1肾小球肾炎模型，分析了β-肾上腺素能阻滞剂（与血管紧张素转换酶抑制剂相比）对促纤维化细胞因子转化生长因子（TGF）-β在肾脏中过表达的作用。
在诱导抗thy1肾小球肾炎一天后，给大鼠给予递增剂量的β-阻滞剂美托洛尔或奈必洛尔（已知血压剂量的0.1倍、1倍、10倍和20倍），持续至第6天，20倍剂量持续至第12天。另外的动物用高剂量的血管紧张素转换酶抑制剂依那普利进行治疗。在每个实验结束时，记录血压和心率，通过组织学对肾小球基质扩张进行评分，并在培养的肾小球上清液中测定TGF-β(1)、纤连蛋白和纤溶酶原激活物抑制剂-1的蛋白表达。
美托洛尔和奈必洛尔以剂量依赖的方式降低心率。未治疗动物的血压正常，两种治疗均未对其产生显著影响。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使TGF-β(1)过表达发生显著变化。相比之下，依那普利在疾病诱导后第6天和第12天均使TGF-β(1)水平显著降低（分别降低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产生的变化与TGF-β(1)的表达密切相关。
在急性和血压正常的肾小球纤维化模型中，β-肾上腺素能拮抗作用不会降低TGF-β的过表达，这表明其不依赖血压的抗纤维化作用可能仅限于慢性肾病。血管紧张素II抑制即使对急性基质扩张也具有有益作用，这可能是解释其在治疗纤维化肾病方面优越性的一个相关机制。
