Mezzano Sergio A, Aros Claudio A, Droguett Alejandra, Burgos M Eugenia, Ardiles Leopoldo G, Flores Claudio A, Carpio Daniel, Vío Carlos P, Ruiz-Ortega Marta, Egido Jesús
Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile.
Kidney Int Suppl. 2003 Oct(86):S39-45. doi: 10.1046/j.1523-1755.64.s86.8.x.
The molecular mechanisms of renal injury and fibrosis in proteinuric nephropathies are not completely elucidated but the renin-angiotensin system (RAS) is involved. Idiopathic membranous nephropathy (MN), a proteinuric disease, may progress to renal failure. Our aim was to investigate the localization of RAS components in MN and their correlation with profibrotic parameters and renal injury.
Renal biopsies from 20 patients with MN (11 with progressive disease) were studied for the expression of RAS components [angiotensin-converting enzyme (ACE) and angiotensin II (Ang II)] by immunohistochemistry. Transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF)-BB were studied by by in situ hybridization, and myofibroblast transdifferentiation by alpha-smooth muscle actin (alpha-SMA) staining.
ACE immunostaining was elevated in tubular cells and appeared in interstitial cells colocalized in alpha-actin-positive cells in progressive disease. Elevated levels of Ang II were observed in tubules and infiltrating interstitial cells. TGF-beta and PDGF mRNAs were up-regulated mainly in cortical tubular epithelial cells in progressive disease (P < 0.01) and correlated with the myofibroblast transdifferentiation (r = 0.8, P < 0.01 for TGF-beta; r = 0.6, P < 0.01 for PDGF). Moreover, in serial sections of progressive cases, the ACE and Ang II over-expression was associated with the tubular expression of these pro-fibrogenic factors, and with the interstitial infiltration and myofibroblast activation.
Intrarenal RAS is selectively activated in progressive MN. De novo expression of ACE at sites of tubulointerstitial injury suggests that the in situ Ang II generation could participate in tubular TGF-beta up-regulation, epithelial-myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulointerstitial injury.
蛋白尿性肾病中肾损伤和纤维化的分子机制尚未完全阐明，但肾素-血管紧张素系统（RAS）参与其中。特发性膜性肾病（MN）是一种蛋白尿性疾病，可能进展为肾衰竭。我们的目的是研究RAS成分在MN中的定位及其与促纤维化参数和肾损伤的相关性。
对20例MN患者（11例为进行性疾病）的肾活检组织进行免疫组织化学研究，以检测RAS成分[血管紧张素转换酶（ACE）和血管紧张素II（Ang II）]的表达。通过原位杂交研究转化生长因子-β（TGF-β）和血小板衍生生长因子（PDGF）-BB，并通过α-平滑肌肌动蛋白（α-SMA）染色研究肌成纤维细胞转分化。
在进行性疾病中，ACE免疫染色在肾小管细胞中升高，并出现在与α-肌动蛋白阳性细胞共定位的间质细胞中。在肾小管和浸润的间质细胞中观察到Ang II水平升高。TGF-β和PDGF mRNA主要在进行性疾病的皮质肾小管上皮细胞中上调（P<0.01），并与肌成纤维细胞转分化相关（TGF-β的r=0.8，P<0.01；PDGF的r=0.6，P<0.01）。此外，在进行性病例的连续切片中，ACE和Ang II的过表达与这些促纤维化因子的肾小管表达、间质浸润和肌成纤维细胞活化相关。
在进行性MN中，肾内RAS被选择性激活。ACE在肾小管间质损伤部位的新生表达表明，原位生成的Ang II可能参与肾小管TGF-β上调上皮-肌成纤维细胞转分化和疾病进展。这些结果提示Ang II在人类肾小管间质损伤中具有新的作用。
