title: HGF gene therapy attenuates renal allograft scarring by preventing the profibrotic inflammatory-induced mechanisms.
abstract: 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.
authors.affiliation: Laboratory of Experimental Nephrology, Department of Medicine, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain. iherrero@ub.edu
authors.forename: I
authors.initials: I
authors.lastname: Herrero-Fresneda
authors.forename: J
authors.initials: J
authors.lastname: Torras
authors.forename: M
authors.initials: M
authors.lastname: Franquesa
authors.forename: A
authors.initials: A
authors.lastname: Vidal
authors.forename: J M
authors.initials: JM
authors.lastname: Cruzado
authors.forename: N
authors.initials: N
authors.lastname: Lloberas
authors.forename: C
authors.initials: C
authors.lastname: Fillat
authors.forename: J M
authors.initials: JM
authors.lastname: Grinyó
mesh_terms: D000818:Animals; D015415:Biomarkers; D002921:Cicatrix / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D016030:Kidney Transplantation; D008297:Male; D009393:Nephritis / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D011183:Postoperative Complications / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D011507:Proteinuria / Q000473:pathology / Q000601:surgery / Q000628:therapy; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D051996:Transcription Factor RelA / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D015415:Biomarkers; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma