Herrero-Fresneda I, Torras J, Franquesa M, Vidal A, Cruzado J M, Lloberas N, Fillat C, Grinyó J M
Laboratory of Experimental Nephrology, Department of Medicine, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain.
Kidney Int. 2006 Jul;70(2):265-74. doi: 10.1038/sj.ki.5001510. Epub 2006 May 17.
Inflammatory processes and tissue scarring are characteristic features of chronic allograft nephropathy. Hepatocyte growth factor (HGF) has beneficial effects on renal fibrosis and it also ameliorates renal interstitial inflammation as it has been recently described. Contrarily to protein administration, intramuscular gene electrotransfer allows sustained release of HGF. So, here we hypothesized that gene therapy with human HGF would diminish the characteristic scarring of chronic allograft nephropathy either by antagonizing tissue fibrosis mechanisms or by reducing inflammation. Lewis rats transplanted with cold preserved Fischer kidneys received vehicle (NoHGF) or intramuscular plasmid DNA encoding HGF plus electroporation either before transplantation (IniHGF, early post-transplant cytoprotection of tubular cells) or 8/10 weeks after transplantation (DelHGF, delayed prevention of chronic mechanisms). Serum creatinine and proteinuria were measured every 4 weeks for 24 weeks. Grafts at 12 or 24 weeks were evaluated for glomerulosclerosis, fibrosis inflammatory cells and mediators, cell regeneration and tubulo-interstitial damage. Nontreated animals developed renal insufficiency, progressive proteinuria and fibrosis among other characteristic histological features of chronic allograft nephropathy. Treatment with human HGF, especially when delayed until the onset of fibrogenic mechanisms, reduced renal failure and mortality, diminished tubule-interstitial damage, induced cell regeneration, decreased inflammation, NF-kappaB activation, and profibrotic markers at 12 weeks and prevented late interstitial fibrosis and glomerulosclerosis. The effectiveness of HGF-gene therapy in the prevention of renal allograft scarring is related with the halt of profibrotic inflammatory-induced mechanisms.
炎症过程和组织瘢痕形成是慢性移植肾肾病的特征性表现。肝细胞生长因子（HGF）对肾纤维化具有有益作用，并且最近研究表明它还能改善肾间质炎症。与蛋白质给药不同，肌肉内基因电转染可使HGF持续释放。因此，我们在此假设，用人HGF进行基因治疗可通过拮抗组织纤维化机制或减轻炎症来减少慢性移植肾肾病的特征性瘢痕形成。将冷保存的Fischer肾移植给Lewis大鼠，在移植前（IniHGF，对肾小管细胞的早期移植后细胞保护）或移植后8/10周（DelHGF，对慢性机制的延迟预防）给予载体（NoHGF）或编码HGF的肌肉内质粒DNA并进行电穿孔。每4周测量一次血清肌酐和蛋白尿，共测量24周。对12周或24周时的移植物进行肾小球硬化、纤维化、炎性细胞和介质、细胞再生以及肾小管间质损伤的评估。未治疗的动物出现肾功能不全、进行性蛋白尿和纤维化以及慢性移植肾肾病的其他特征性组织学表现。用人HGF治疗，尤其是延迟至纤维化机制开始时进行治疗，可降低肾衰竭和死亡率，减轻肾小管间质损伤，诱导细胞再生，减轻炎症、核因子κB激活以及12周时的促纤维化标志物，并预防晚期间质纤维化和肾小球硬化。HGF基因治疗在预防移植肾瘢痕形成方面的有效性与阻止促纤维化炎症诱导机制有关。
