Fibrosis Research Laboratory, Division of Nephrology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Am J Physiol Renal Physiol. 2011 Oct;301(4):F723-32. doi: 10.1152/ajprenal.00271.2011. Epub 2011 Jul 27.
The limited antifibrotic effect of therapeutic angiotensin blockade, the fact that angiotensin blockade dramatically elevates renin levels, and recent evidence that renin has an angiotensin-independent, receptor-mediated profibrotic action led us to hypothesize that combining renin receptor inhibition and ANG II blockade would increase the antifibrotic effect of angiotensin blockade alone. Using cultured nephritic glomeruli from rats with anti-Thy-1-induced glomerulonephritis, the maximally effective dose of enalaprilate was determined to be 10(-4) M, which reduced mRNAs for transforming growth factor (TGF)-β1, fibronectin (FN), and plasminogen activator inhibitor-1 (PAI-1) by 49, 65, and 56% and production of TGF-β1 and FN proteins by 60 and 49%, respectively. Disease alone caused 6.8-fold increases in ANG II levels that were reduced 64% with enalaprilate. In contrast, two- and threefold disease-induced increases in renin mRNA and activity were further increased 2- and 3.7-fold with 10(-4) M enalaprilate treatment. Depressing the renin receptor by 80% with small interfering (si) RNA alone reduced fibrotic markers in a manner remarkably similar to enalaprilate alone but had no effect on glomerular renin expression. Enalaprilate and siRNA combination therapy further reduced disease markers. Notably, elevated TGF-β1 and FN production was reduced by 73 and 81%, respectively. These results support the notion of a receptor-mediated profibrotic action of renin, suggest that the limited effectiveness of ANG II blockade may be due, at least in part, to the elevated renin they induce, and support our hypothesis that adding renin receptor inhibitor to ANG II blockade in patients may have therapeutic potential.
血管紧张素转换酶抑制剂（ACEI）治疗的抗纤维化作用有限，血管紧张素转换酶抑制剂（ACEI）显著提高肾素水平，以及最近的证据表明肾素具有血管紧张素非依赖性、受体介导的促纤维化作用，这使我们假设联合使用肾素受体抑制剂和血管紧张素 II 阻断剂会增加血管紧张素阻断剂的单独抗纤维化作用。在抗 Thy-1 诱导的肾小球肾炎大鼠培养的肾小球中，确定依那普利的最大有效剂量为 10(-4) M，该剂量使转化生长因子（TGF）-β1、纤维连接蛋白（FN）和纤溶酶原激活物抑制剂-1（PAI-1）的 mRNA 分别减少 49%、65%和 56%，TGF-β1 和 FN 蛋白的产生分别减少 60%和 49%。疾病本身导致 ANG II 水平增加了 6.8 倍，依那普利使 ANG II 水平降低了 64%。相比之下，疾病引起的肾素 mRNA 和活性增加了两到三倍，用 10(-4) M 依那普利处理后进一步增加了 2 到 3.7 倍。单独用小干扰（si）RNA 抑制肾素受体使纤维化标志物减少了 80%，这与依那普利单独作用非常相似，但对肾小球肾素表达没有影响。依那普利和 siRNA 联合治疗进一步降低了疾病标志物。值得注意的是，TGF-β1 和 FN 的产生分别减少了 73%和 81%。这些结果支持肾素具有受体介导的促纤维化作用的观点，表明 ANG II 阻断的有限效果可能至少部分归因于它们诱导的肾素升高，并支持我们的假设，即在患者中添加肾素受体抑制剂与 ANG II 阻断剂联合使用可能具有治疗潜力。
