Electroporation-mediated HGF gene transfer ameliorated cyclosporine nephrotoxicity
Electroporation-mediated HGF gene transfer ameliorated cyclosporine nephrotoxicity
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DOI：
10.1111/j.1523-1755.2004.00625.x
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发表时间：
2004-06-01
影响因子：
19.6
通讯作者：
Hori, M
中科院分区：
文献类型：
--
作者：
Mizui, M;Isaka, Y;Hori, M
背景。环孢素 A (CsA) 的临床应用因其肾毒性而受到限制，其特点是肾小管萎缩、间质纤维化和进行性肾功能损害。据报道，肝细胞生长因子（HGF）作为促肾和抗纤维化因子可以保护和挽救肾损伤。在这里，我们利用电穿孔介导的基因转移研究了 HGF 基因治疗对大鼠 CsA 诱导的肾毒性的保护作用。在低钠饮食下每天皮下注射CsA，并在第7天和第14天通过电穿孔将HGF基因转移到骨骼肌中。我们还使用人近端肾小管上皮细胞检查了HGF的抗凋亡机制。结果。 HGF 基因转移可挽救 CsA 诱导的初始肾小管损伤，并抑制 CsA 诱导的肾毒性中 ED-1 阳性巨噬细胞的间质浸润。此外，HGF显着抑制肾小管细胞凋亡，并增加增殖的肾小管上皮细胞的数量。体外研究表明，HGF 通过增强 Akt 和 Bcl-2 的磷酸化来发挥抗凋亡功能。 Northern印迹分析表明，HGF基因转移抑制了皮质转化生长因子-β（TGF-β）的mRNA水平。因此，HGF基因转移显着减少了条纹间质表型改变和纤维化。结论。我们证明 HGF 基因转移减少了 CsA 诱导的肾小管细胞凋亡和间质纤维化。 HGF 基因转移可能是预防肾纤维化的潜在策略。
Background. The clinical utility of cyclosporine A (CsA) has been limited by its nephrotoxicity, which is characterized by tubular atrophy, interstitial fibrosis, and progressive renal impairment. Hepatocyte growth factor (HGF) has been reported to protect and salvage from renal injury as a renotropic and antifibrotic factor. Here, we investigated protective effects of HGF gene therapy on rat CsA-induced nephrotoxicity using electroporation-mediated gene transfer.Method. CsA was subcutaneously administered daily under low sodium diet, and HGF gene was transferred into skeletal muscle by electroporation on days 7 and 14. We also examined the antiapoptotic mechanism of HGF using human proximal tubular epitherial cells.Results. HGF gene transfer rescued CsA-induced initial tubular injury and suppressed interstitial infiltration of ED-1-positive macrophages in CsA-induced nephrotoxicity. In addition, HGF significantly inhibited tubular cell apoptosis, and increased the number of proliferating tubular epithelial cells. In vitro studies suggest that HGF executes the antiapoptotic function by enhancing the phosphorylation of Akt and Bcl-2. Northern blot analysis demonstrated that HGF gene transfer suppressed cortical mRNA levels of transforming growth factor-beta (TGF-beta).Consequently, HGF gene transfer significantly reduced a striped interstitial phenotypic alteration and fibrosis. Conclusion. We demonstrated that HGF gene transfer reduced CsA-induced tubular cell apoptosis and interstitial fibrosis. HGF gene transfer could be a potential strategy for preventing renal fibrosis.