Picard Nicolas, Baum Oliver, Vogetseder Alexander, Kaissling Brigitte, Le Hir Michel
Anatomical Institute, University of Zürich, Winterthurestr. 190, 8057, Zurich, Switzerland.
Histochem Cell Biol. 2008 Jul;130(1):141-55. doi: 10.1007/s00418-008-0433-8. Epub 2008 May 1.
Tubulo-interstitial fibrosis is a constant feature of chronic renal failure and it is suspected to contribute importantly to the deterioration of renal function. In the fibrotic kidney there exists, besides normal fibroblasts, a large population of myofibroblasts, which are supposedly responsible for the increased production of intercellular matrix. It has been proposed that myofibroblasts in chronic renal failure originate from the transformation of tubular cells via epithelial-mesenchymal transition (EMT) or from infiltration by bone marrow-derived precursors. Little attention has been paid to the possibility of a transformation of resident fibroblasts into myofibroblasts in renal fibrosis. Therefore we examined the fate of resident fibroblasts in the initial phase of renal fibrosis in the classical model of unilateral ureter obstruction (UUO) in the rat. Rats were perfusion-fixed on days 1, 2, 3 and 4 after ligature of the right ureter. Starting from 1 day of UUO an increasing expression of alpha-smooth muscle actin (alphaSMA) in resident fibroblasts was revealed by immunofluorescence and confirmed by the observation of bundles of microfilaments and webs of intermediate filaments in the electron microscope. Inversely, there was a decreased expression of 5'-nucleotidase (5'NT), a marker of renal cortical fibroblasts. The RER became more voluminous, suggesting an increased synthesis of matrix. Intercellular junctions, a characteristic feature of myofibroblasts, became more frequent. The mitotic activity in fibroblasts was strongly increased. Renal tubules underwent severe regressive changes but the cells retained their epithelial characteristics and there was no sign of EMT. In conclusion, after ureter ligature, resident peritubular fibroblasts proliferated and they showed progressive alterations, suggesting a transformation in myofibroblasts. Thus the resident fibroblasts likely play a central role in fibrosis in that model.
肾小管间质纤维化是慢性肾衰竭的一个常见特征，据推测它对肾功能恶化起着重要作用。在纤维化的肾脏中，除了正常的成纤维细胞外，还存在大量的肌成纤维细胞，据认为这些细胞是细胞间基质产生增加的原因。有人提出，慢性肾衰竭中的肌成纤维细胞起源于肾小管细胞通过上皮-间质转化（EMT）的转变，或源于骨髓来源的前体细胞的浸润。在肾纤维化过程中，驻留的成纤维细胞转化为肌成纤维细胞的可能性很少受到关注。因此，我们在大鼠单侧输尿管梗阻（UUO）的经典模型中，研究了肾纤维化初始阶段驻留成纤维细胞的命运。在右侧输尿管结扎后的第1、2、3和4天对大鼠进行灌注固定。从UUO第1天开始，通过免疫荧光显示驻留成纤维细胞中α-平滑肌肌动蛋白（αSMA）的表达增加，并通过电子显微镜观察微丝束和中间丝网络得到证实。相反，5'-核苷酸酶（5'NT）的表达降低，5'NT是肾皮质成纤维细胞的标志物。粗面内质网变得更加丰富，表明基质合成增加。细胞间连接是肌成纤维细胞的一个特征性特征，变得更加频繁。成纤维细胞的有丝分裂活性显著增加。肾小管发生严重的退行性变化，但细胞保留了其上皮特征，没有EMT的迹象。总之，输尿管结扎后，驻留的肾小管周成纤维细胞增殖并表现出渐进性改变，提示向肌成纤维细胞转化。因此，在该模型中，驻留的成纤维细胞可能在纤维化中起核心作用。
