Yang Junwei, Dai Chunsun, Liu Youhua
Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
J Am Soc Nephrol. 2002 Oct;13(10):2464-77. doi: 10.1097/01.asn.0000031827.16102.c1.
Tubulointerstitial fibrosis is considered to be common endpoint result of many forms of chronic renal diseases. Except for renal replacement, chronic renal fibrosis is presently incurable. This study demonstrates that the combination of hepatocyte growth factor (HGF) gene therapy with inhibition of the renin-angiotensin system produced synergistic beneficial effects leading to dramatic attenuation of renal tubulointerstitial fibrosis in obstructive nephropathy in mice. The combined treatment with human HGF gene and losartan, an angiotensin II (AngII) type I receptor blocker, preserved renal mass and gross morphology of the obstructed kidneys. Although HGF gene therapy alone inhibited the expression of alpha-smooth muscle actin (alpha SMA) by approximately 54% and 60% at day 7 and day 14 after surgery, respectively, its combination with losartan almost completely abolished alpha SMA induction in the obstructed kidneys. The combined therapy also synergistically inhibited the accumulation of interstitial matrix components, such as fibronectin and collagen I, and suppressed renal expression of transforming growth factor-beta1 (TGF-beta1) and its type I receptor. In vitro studies revealed that AngII by itself did not induce alpha SMA, but it drastically potentiated TGF-beta1-initiated alpha SMA expression in tubular epithelial cells. Furthermore, HGF abrogated de novo alpha SMA expression induced by TGF-beta1 plus AngII. These results suggest that many factors are implicated in the pathogenesis of renal interstitial fibrosis; therefore, a combined therapy aimed at simultaneously targeting multiple pathologic pathways may be necessary for halting the progression of chronic renal diseases. These findings may provide the basis for designing future therapeutic regimens for blocking progressive renal fibrosis in patients.
肾小管间质纤维化被认为是多种慢性肾脏疾病的常见终点结果。除了肾脏替代治疗外，慢性肾纤维化目前无法治愈。本研究表明，肝细胞生长因子（HGF）基因治疗与肾素 - 血管紧张素系统抑制相结合产生协同有益作用，导致小鼠梗阻性肾病中肾小管间质纤维化显著减轻。人HGF基因与血管紧张素II（AngII）I型受体阻滞剂氯沙坦联合治疗可保留梗阻肾脏的肾实质和大体形态。尽管单独的HGF基因治疗在术后第7天和第14天分别使α - 平滑肌肌动蛋白（αSMA）的表达抑制约54%和60%，但其与氯沙坦联合几乎完全消除了梗阻肾脏中αSMA的诱导。联合治疗还协同抑制了间质基质成分如纤连蛋白和I型胶原的积累，并抑制了转化生长因子 - β1（TGF - β1）及其I型受体在肾脏中的表达。体外研究表明，AngII本身不诱导αSMA，但它显著增强了TGF - β1引发的肾小管上皮细胞中αSMA的表达。此外，HGF消除了由TGF - β1加AngII诱导的新生αSMA表达。这些结果表明，许多因素参与了肾间质纤维化的发病机制；因此，针对多种病理途径同时进行靶向治疗可能是阻止慢性肾脏疾病进展所必需的。这些发现可能为设计未来阻断患者进行性肾纤维化的治疗方案提供依据。
