Anti-inflammatory effect of hepatocyte growth factor in chronic kidney disease: Targeting the inflamed vascular endothelium
Anti-inflammatory effect of hepatocyte growth factor in chronic kidney disease: Targeting the inflamed vascular endothelium
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DOI：
10.1681/asn.2006020185
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发表时间：
2006-09-01
影响因子：
13.6
通讯作者：
Dworkin, Lance D.
中科院分区：
文献类型：
--
作者：
Gong, Rujun;Rifai, Abdalla;Dworkin, Lance D.
最近的研究表明，肝细胞生长因子（HGF）在包括肾脏在内的多种器官系统疾病的动物模型中具有有效的抗炎作用，表明HGF可能抑制常见的促炎过程。本研究旨在探讨慢性肾脏疾病模型中HGF抗炎作用的分子机制。从肾次全切除术后2周开始，大鼠连续输注重组HGF，通过每日注射抗HGF抗体或免疫前IgG来中和内源性HGF，再持续2周。观察其对炎症和损伤的影响。HGF的使用改善了残余肾脏的炎症，而中和内源性HGF加重了残余肾脏的炎症。这伴随着内皮活化和炎症的平行改变，分别以肾血管内皮中e -选择素的新生表达和白细胞对内皮的粘附为标志。在体外，HGF可破坏单核细胞对tnf - α激活的内皮单层的粘附，抑制内皮细胞中e -选择素的表达，而e -选择素的表达依赖于nf - κ B信号传导。此外，HGF抑制tnf - α诱导的NF-kappa B报告基因活性，并在e -选择素基因水平上抵消tnf - α诱导的NF-kappa B与kappa B元件的相互作用。对NF-kappa B信号级联的解剖发现，抑制NF-kappa B依赖于HGF对NF-kappa B和I -kappa B磷酸化和I -kappa B降解的抑制作用。在体内，持续输注外源性HGF显著减少残余肾脏中循环荧光标记巨噬细胞的隔离，模仿e-选择素阻断抗体的作用。这些发现表明，HGF在抑制nf - κ B活化和下游内皮炎症的基础上具有有效和直接的抗炎作用。
Recent studies show that hepatocyte growth factor (HGF) has potent anti-inflammatory effects in multiple animal models of disease in various organ systems, including the kidney, suggesting that HGF may suppress a common proinflammatory process. The aim of this study was to examine the molecular mechanism of HGF's anti-inflammatory actions in a model of chronic kidney disease. Beginning 2 wk after subtotal nephrectomy, rats received a continuous infusion of recombinant HGF, neutralization of endogenous HGF by daily injection of an anti-HGF antibody, or preimmune IgG for an additional 2 wk. The effects on inflammation and injury were examined. HGF administration ameliorated whereas neutralizing endogenous HGF worsened renal inflammation in remnant kidneys. This was accompanied by parallel alterations in endothelial activation and inflammation, marked respectively by de novo E-selectin expression in renal vascular endothelium and leukocyte adhesion to endothelium. In vitro, HGF abrogated monocyte adhesion to TNF-alpha-activated endothelial monolayers and suppressed endothelial expression of E-selectin, which depended on NF-kappa B signaling. In addition, HGF suppressed NF-kappa B reporter gene activity that was induced by TNF-alpha and counteracted TNF-alpha-elicited NF-kappa B interaction with kappa B elements at the E-selectin gene level. Dissection of the NF-kappa B signaling cascade revealed that suppression of NF-kappa B depended on HGF's inhibitory action on NF-kappa B and I kappa B phosphorylation and I kappa B degradation. In vivo, continuous infusion of exogenous HGF markedly diminished sequestration of circulating fluorescence-labeled macrophages in the remnant kidney, mimicking the action of an E-selectin blocking antibody. These findings suggest that HGF has potent and direct anti-inflammatory effects on the basis of suppression of NF-kappa B activation and downstream endothelial inflammation.