Single injection of naked plasmid encoding hepatocyte growth factor prevents cell death and ameliorates acute renal failure in mice
Single injection of naked plasmid encoding hepatocyte growth factor prevents cell death and ameliorates acute renal failure in mice
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DOI：
10.1681/asn.v132411
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发表时间：
2002-02-01
影响因子：
13.6
通讯作者：
Liu, YH
中科院分区：
文献类型：
--
作者：
Dai, CS;Yang, JW;Liu, YH
肝细胞生长因子（HGF）是一种多效因子，在损伤后的组织修复和再生中发挥重要作用。叶酸引起的急性肾损伤后，HGF及其c-met受体基因的表达迅速上调。在本研究中，通过在小鼠体内全身施用含有巨细胞病毒启动子驱动的人 HGF cDNA (pCMV-HGF) 的裸质粒，检查了外源性 HGF 在预防急性肾衰竭中的作用。静脉注射pCMV-HGF质粒在小鼠肾脏中产生大量的人HGF蛋白。同时注射HGF质粒DNA可显着改善肾功能障碍并加速叶酸引起的急性损伤的恢复。有趣的是，在叶酸注射前 24 小时预施用 HGF 质粒可显着保护肾上皮细胞免于凋亡和坏死，并保持肾小管结构和功能的完整性。 HGF 转基因的表达激活蛋白激酶 B/Akt 激酶并保留体内促存活 Bcl-xL 蛋白表达。这些结果表明，单次静脉注射含有HGF基因的裸质粒不仅可以促进损伤后的肾脏再生，而且可以首先保护肾小管上皮细胞免受最初的损伤和细胞死亡。这些数据表明HGF基因治疗可能为探索临床急性肾衰竭的新治疗策略提供新途径。
Hepatocyte growth factor (HGF) is a pleiotrophic factor that plays an important role in tissue repair and regeneration after injury. The expression of both HGF and its c-met receptor genes is rapidly upregulated after acute renal injury induced by folic acid. In this study, the role of exogenous HGF in preventing acute renal failure by systemic administration of naked plasmid containing human HGF cDNA driven under the cytomegalovirus promoter (pCMV-HGF) was examined in mice. Intravenous injection of pCMV-HGF plasmid produced substantial levels of human HGF protein in mouse kidneys. Simultaneous injection of HGF plasmid DNA significantly ameliorated renal dysfunctions and accelerated recovery from the acute injury induced by folic acid. Of interest, preadministration of HGF plasmid 24 h before folic acid injection dramatically protected renal epithelial cells from both apoptotic and necrotic death and preserved the structural and functional integrity of renal tubules. Expression of HGF transgene activated protein kinase B/Akt kinase and preserved prosurvival Bcl-xL protein expression in vivo. These results indicate that a single, intravenous injection of naked plasmid containing HGF gene not only promotes renal regeneration after injury but also protects tubular epithelial cells from the initial injury and cell death in the first place. These data suggest that HGF gene therapy may provide a new avenue for exploring a novel therapeutic strategy for clinical acute renal failure.