Abstract
The annual rate of kidney graft loss caused by chronic allograft nephropathy (CAN) has not improved over the past decade. Recent reports suggest that acute renal ischemia results in development of CAN. The goal of the present study was to assess the renoprotective potential and safety of hepatocyte growth factor (HGF) gene transfer using a porcine kidney transplant warm ischemia injury model. Following left porcine kidney removal, 10 min of warm ischemic injury was intentionally induced. Next, the HGF expression vector or vehicle was infused into the renal artery with the renal vein clamped ex vivo, and electric pulses were discharged using bathtub-type electrodes. Kidney grafts were then transplanted after removing the right kidney. Histopathological examination of vehicle-transfected kidney transplant revealed initial tubular injury followed by tubulointerstitial fibrosis. In contrast, HGF-transfected kidneys showed no initial tubular damage and no interstitial fibrosis at 6 months post-transplant. We conclude that electroporation-mediated ex vivo HGF gene transfection protects the kidney against graft injury in a porcine model.
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References
Halloran PF, Melk A, Barth C . Rethinking chronic allograft nephropathy: the concept of accelerated senescence. J Am Soc Nephrol 1999; 10: 167–181.
Azuma H et al. Nephron mass modulates the hemodynamic, cellular, and molecular response of the rat renal allograft. Transplantation 1997; 63: 519–528.
Azuma H et al. Hepatocyte growth factor prevents the development of chronic allograft nephropathy in rats. J Am Soc Nephrol 2001; 12: 1280–1292.
Liu ML, Mars WM, Zarnegar R, Michalopoulos GK . Uptake and distribution of hepatocyte growth factor in normal and regenerating adult rat liver. Am J Pathol 1994; 144: 129–140.
Yazawa K et al. Direct transfer of hepatocyte growth factor gene into kidney suppresses cyclosporin A nephrotoxicity in rats. Nephrol Dial Transplant 2004; 19: 812–816.
Kawaida K, Matsumoto K, Shimazu H, Nakamura T . Hepatocyte growth factor prevents acute renal failure and accelerates renal regeneration in mice. Proc Natl Acad Sci USA 1994; 91: 4357–4361.
Matsumoto K, Nakamura T . Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases. Kidney Int 2001; 59: 2023–2038.
Tsujie M et al. Electroporation-mediated gene transfer that targets glomeruli. J Am Soc Nephrol 2001; 12: 949–954.
Racusen LC et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55: 713–723.
Solez K et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 1993; 44: 411–422.
Nakamura T et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342: 440–443.
Nakamura T, Teramoto H, Ichihara A . Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary cultures. Proc Natl Acad Sci USA 1986; 83: 6489–6493.
Amaike H, Matsumoto K, Oka T, Nakamura T . Preventive effect of hepatocyte growth factor on acute side effects of cyclosporin A in mice. Cytokine 1996; 8: 387–394.
Miller SB, Martin DR, Kissane J, Hammerman MR . Hepatocyte growth factor accelerates recovery from acute ischemic renal injury in rats. Am J Physiol 1994; 266: F129–F134.
Liu Y . Hepatocyte growth factor promotes renal epithelial cell survival by dual mechanisms. Am J Physiol 1999; 277: F624–F633.
Mizuno S, Matsumoto K, Nakamura T . Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy. Kidney Int 2001; 59: 1304–1314.
Mizuno S et al. Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease. J Clin Invest 1998; 101: 1827–1834.
Tsujie M et al. Prolonged transgene expression in glomeruli using an EBV replicon vector system combined with HVJ liposomes. Kidney Int 2001; 59: 1390–1396.
Niwa H, Yamamura K, Miyazaki J . Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 1991; 108: 193–199.
Gao X et al. Hepatocyte growth factor gene therapy retards the progression of chronic obstructive nephropathy. Kidney Int 2002; 62: 1238–1248.
Acknowledgements
This work was supported by grant from Grant-in-Aid for the Development of Innovative Technology. We thank Dr Isabel McMorrow for critical review of the manuscript.
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Isaka, Y., Yamada, K., Takabatake, Y. et al. Electroporation-mediated HGF gene transfection protected the kidney against graft injury. Gene Ther 12, 815–820 (2005). https://doi.org/10.1038/sj.gt.3302478
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DOI: https://doi.org/10.1038/sj.gt.3302478
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