Endogenous hepatocyte growth factor ameliorates chronic renal injury by activating matrix degradation pathways
Endogenous hepatocyte growth factor ameliorates chronic renal injury by activating matrix degradation pathways
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DOI：
10.1111/j.1523-1755.2000.00375.x
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发表时间：
2000-11-01
影响因子：
19.6
通讯作者：
Dworkin, LD
中科院分区：
文献类型：
--
作者：
Liu, YH;Rajur, K;Dworkin, LD
背景：肝细胞生长因子(HGF)可促进急性肾损伤后肾小管的修复和再生；然而，HGF是否也调节以进行性组织纤维化为特征的慢性肾脏疾病的发生和发展尚不确定。为了检验这个问题，这项研究调查了在慢性肾脏疾病模型中阻断体内内源性HGF信号的功能后果。观察HGF对体外培养的肾上皮细胞基质合成和降解过程的影响。观察大鼠5/6肾切除后不同时间点肝细胞生长因子/c-MET轴的活性水平。为确定肝细胞生长因子对慢性肾损伤的调节作用，用抗肝细胞生长因子抗体阻断残肾大鼠肝细胞生长因子的作用。采用S-35-蛋氨酸标记、Western blotting和酶谱分析等方法检测肝细胞生长因子对肾上皮细胞细胞外基质合成和降解的影响。在残留肾脏的大鼠中，观察到肾脏和全身HGF的产生增加，同时肾脏c-met的增加。当给予抗HGF抗体阻断HGF的作用时，大鼠经历了肾小球滤过率的迅速下降和肾脏纤维化的增加。抗体处理的大鼠肾脏切片显示细胞外基质积聚显著增加，间质和肾小管上皮细胞中或-平滑肌肌动蛋白阳性细胞明显增加。体外研究表明，HGF减少了人近端小管细胞(HKC)细胞外基质的净积聚，这种作用可被抗HGF抗体孵育的细胞所消除。HGF不改变HKC细胞的ECM合成速率。相反，Western blotting和酶谱分析表明，它显著增加了胶原酶，如基质金属蛋白酶-9(MMP9)的蛋白表达。肝细胞生长因子还可降低基质金属蛋白酶组织抑制因子L(TIMP-1)和TIMP-2的表达。这些结果表明，HGF在体外和体内都是一种有效的抗纤维化因子。内源性激活HGF可能通过激活基质降解途径来保护慢性肾脏疾病大鼠的肾脏结构和功能。
Background Hepatocyte growth factor (HGF) has been shown to promote tubule repair and renal regeneration following acute injury; however, whether HGF also modulates the development and progression of chronic renal diseases that are characterized by progressive tissue fibrosis is uncertain. To examine this question, this study investigated the functional consequence of blocking endogenous HGF signaling in vivo in a model of chronic renal disease. The effects of HGF on the processes of matrix synthesis and degradation in cultured renal epithelial cells were also examined.Methods. The level of activity of the HGF/c-met axis was examined in rats following 5/6 nephrectomy at multiple time points. To determine the effects of HGF in modulating chronic renal injury, HGF action was blocked in remnant kidney rats using an anti-HGF antibody. The effects of HGF on extracellular matrix (ECM) synthesis and degradation were examined in renal epithelial cells by S-35-methionine labeling, Western blotting, and zymographic analysis.Results. An increase in renal and systemic production of HGF coupled with an increase in renal c-met was observed in rats with remnant kidneys. When HGF action was blocked by the administration of an anti-HGF antibody, rats experienced a rapid decrease in glomerular filtration rate and increased renal fibrosis. Kidney sections from the antibody-treated rats displayed a marked increase in ECM accumulation and in or-smooth muscle actin-positive cells in both the interstitium and tubular epithelium. In vitro studies revealed that HGF reduced net ECM accumulation by human proximal tubule cells (HKC), and this effect was abolished by incubating cells with an anti-HGF antibody. HGF did not alter the ECM synthetic rate in HKC cells. Rather, it markedly increased collagenase such as matrix metalloproteinase-9 (MMP-9) protein expression, as evidenced by Western blotting and zymographic analysis. HGF also decreased the expression of tissue inhibitors of matrix metalloproteinase-l (TIMP-1) and TIMP-2, the endogenous inhibitors of MMPs.Conclusion. These results suggest that HGF is a potent anti-fibrogenic factor both in vitro and in vivo. Endogenous activation of HGF tends to preserve kidney structure and function in rats with chronic renal disease by activating matrix degradation pathways.