Iwano Masayuki, Neilson Eric G
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Curr Opin Nephrol Hypertens. 2004 May;13(3):279-84. doi: 10.1097/00041552-200405000-00003.
Tubulointerstitial fibrosis is the final common pathway to end-stage renal disease. Understanding the mechanisms of tubulointerstitial fibrosis is essential in establishing novel therapeutic strategies for the prevention or arrest of progressive kidney diseases. The present review focuses on a newly proposed mechanism of tubulointerstitial fibrosis, one that emphasizes the roles of epithelial-mesenchymal transition and cellular activation.
Among the cells that accumulate in the renal interstitium, fibroblasts are the principal effectors mediating tubulointerstitial fibrosis. By contrast, the phagocytosis of extracellular matrix and apoptotic cells by macrophages may actually exert a beneficial effect. Interstitial fibroblasts are more heterogeneous than expected, and during renal fibrosis new fibroblasts are derived mainly through epithelial-mesenchymal transition. The intracellular signaling pathways leading to initiation of epithelial-mesenchymal transition remain largely unknown, though recent studies have identified beta-catenin and Smad3 activation of lymphoid enhancer factor, integrin-linked kinase, and small GTPases and mitogen-activated protein kinases as key components. Transforming growth factor-beta is believed to be a critical fibrogenic factor, but recent studies have also focused on transforming growth factor-beta independent pathways as mechanisms of tubulointerstitial fibrosis. As the mechanisms underlying tubulointerstitial fibrosis leading to epithelial-mesenchymal transition have been identified, so have cytokines that efficiently antagonize renal fibrosis, particularly bone morphogenic protein-7 and hepatocyte growth factor.
In combination with traditional angiotensin converting enzyme inhibitors, newly identified cytokines may eventually form the basis for new therapeutic strategies aimed at inhibiting the progression of renal disease.
肾小管间质纤维化是终末期肾病的最终共同途径。了解肾小管间质纤维化的机制对于制定预防或阻止进行性肾脏疾病的新治疗策略至关重要。本综述重点关注一种新提出的肾小管间质纤维化机制，该机制强调上皮-间质转化和细胞活化的作用。
在肾间质中积聚的细胞中，成纤维细胞是介导肾小管间质纤维化的主要效应细胞。相比之下，巨噬细胞对细胞外基质和凋亡细胞的吞噬作用实际上可能具有有益效果。间质成纤维细胞比预期的更具异质性，并且在肾纤维化过程中，新的成纤维细胞主要通过上皮-间质转化产生。尽管最近的研究已确定β-连环蛋白和淋巴样增强因子、整合素连接激酶、小GTP酶和丝裂原活化蛋白激酶的Smad3激活是关键成分，但导致上皮-间质转化启动的细胞内信号通路在很大程度上仍不清楚。转化生长因子-β被认为是一种关键的促纤维化因子，但最近的研究也将重点放在了转化生长因子-β非依赖性途径作为肾小管间质纤维化的机制上。随着导致上皮-间质转化的肾小管间质纤维化潜在机制已被确定，有效拮抗肾纤维化的细胞因子也已确定，特别是骨形态发生蛋白-7和肝细胞生长因子。
与传统的血管紧张素转换酶抑制剂联合使用，新发现的细胞因子最终可能构成旨在抑制肾脏疾病进展的新治疗策略的基础。
