Chronic allograft nephropathy (CAN) is the most common cause of chronic graft dysfunction leading to graft failure, our study investigates the expression and significance of p-Akt in the pathogenesis of CAN in rats. Kidneys of Fisher (F344) rats were orthotopically transplanted into Lewis (LEW) rats. The animals were evaluated at 4, 8, 12, 16, and 24 weeks post-transplantation for renal function and histopathology. Phosphorate Akt (p-Akt) protein expression was determined by Western blot and immunohistological assays. Our data show that 24-h urinary protein excretion in CAN rats increased significantly at week 16 as compared with F344/LEW controls. Allografts got severe interstitial infiltration of mononuclear cells at week 4 and week 8, but it was degraded as the time went on after week 16. Allografts markedly presented with severe interstitial fibrosis (IF) and tubular atrophy at 16 and 24 weeks. p-Akt expression was upregulated in rat kidneys with CAN, and the increase became more significant over time after transplantation. p-Akt expression correlated significantly with 24-h urinary protein excretion, serum creatinine levels, tubulointerstitial mononuclear cells infiltration, smooth muscle cells (SMCs) migration in vascular wall, and IF. It was concluded that p-Akt overexpression might be the key event that involved mononuclear cells infiltration and vascular SMCs migration at early stage, and IF and allograft nephroangiosclerosis at the late stage of CAN pathogenesis in rats.
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The authors thank Xiongfei Gu for excellent technical support. This study was funded by Xiamen Research Grant. This work was supported by American CMB-SUMS Scholars Program (China Medical Board of New York, Grant Number: #98-677) and National Natural Science Foundation of China (Grant Number: 997034), Xiamen Technology Fund, and Guangdong Provincial Natural Science Foundation (Grant Number: 990106).
Chapman, J. R., O’Connell, P. J., & Nankivell, B. J. (2005). Chronic renal allograft dysfunction. Journal of the American Society of Nephrology,16, 3015–3026.CrossRefPubMedGoogle Scholar
Joosten, S. A., Van, K. C., Sijpkens, Y. W., et al. (2004). The pathobiology of chronic allograft nephropathy: Immune-mediated damage and accelerated aging. Kidney International,65, 556–559.CrossRefGoogle Scholar
Jevnikar, A. M., & Mannon, R. B. (2008). Late kidney allograft loss: What we know about it, and what we can do about it. Clinical Journal of the American Society of Nephrology,3(suppl 2), S56–S67.CrossRefPubMedCentralPubMedGoogle Scholar
Campistol, J. M., Boletis, I. N., Dantal, J., et al. (2009). Chronic allograft nephropathy—a clinical syndrome: Early detection and the potential role of proliferation signal inhibitors. Clinical Transplantation,23, 769–777.CrossRefPubMedGoogle Scholar
Najafian, B., & Kasiske, B. L. (2008). Chronic allograft nephropathy. Current Opinion in Nephrology and Hypertension,17(2), 149–155.CrossRefPubMedGoogle Scholar
Stuve, O., Chabot, S., Jung, S. S., et al. (1997). Chemokine-enhanced migration of human peripheral blood mononuclear cells is antagonized by interferon beta-1b through an effect on matrix metalloproteinase-9. Journal of Neuroimmunology,80, 38–46.CrossRefPubMedGoogle Scholar
Maillard, J. L., Favreau, C., & Reboud, R. M. (1995). Role of monocyte/macrophage derived matrix metalloproteinases (gelatinases) in prolonged skin inflammation. Chimica Acta,233, 61–74.CrossRefGoogle Scholar
Hume, D. M., Merrill, J. P., Miller, B. F., et al. (1995). Experiences with renal homotransplantation in the human: Report of nine cases. J Clin invest,34, 327–328.CrossRefGoogle Scholar
Mihatsch, M. J., Ryffel, B., & Gudat, F. (1993). Morphological criteria of chronic rejection: Differential diagnosis including cyclosporine-nephropathy. Transplantation Proceedings,25, 2031–2037.PubMedGoogle Scholar
Reinke, P., Fietze, E., Ode, H. S., et al. (1994). Late acute renal allograft rejection and symptomless cytomegylovirus infection. Lancet,344, 1737–1738.CrossRefPubMedGoogle Scholar
Song, E., Zou, H., Yao, Y., et al. (2002). Early application of Met-RANTES ameliorates chronic allograft nephropathy. Kidney International,61, 676–685.CrossRefPubMedGoogle Scholar
Viklicky, O., Zou, H., Muller, V., et al. (2000). SDZ-RAD prevents manifestation of chronic rejection in rat renal allografts. Transplantation,69(4), 497–502.CrossRefPubMedGoogle Scholar
Isoniemi, H., Krogerus, L., von-Willebrand, E., et al. (1991). Renal immunosuppression. VI. Triple drug therapy versus immunosuppressive double drug combinations: Histological findings in renal allografts. Transplant International,4, 151–156.PubMedGoogle Scholar
Wells, G. M., Catlin, G., Cossins, J. A., et al. (1996). Quantitation of matrix metalloproteinases in cultured rat astrocytes using the polymerase chain reaction with a multi-competitor cDNA standard. GLIA,18, 332–340.CrossRefPubMedGoogle Scholar
Anthony, D. C., Miller, K. M., Fearn, S., et al. (1998). Matrix metalloproteinase expression in an experimentally induced DTH model of mutiple sclerosis in the rat CNS. Journal of Neuroimmunology,87, 62–72.CrossRefPubMedGoogle Scholar
Newby, A. C., Southgate, K. M., & Davies, M. (1994). Extracellular matrix degrading metalloproteinases in the pathogenesis of arteriosclerosis. Basic Research in Cardiology,89, 59–70.PubMedGoogle Scholar
Bendeck, M. P., Zempo, N., Clowes, A. W., et al. (1994). Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circulation Research,75, 539–545.CrossRefPubMedGoogle Scholar
Galis, Z. S., Johnson, C., Godin, D., et al. (2002). Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circulation Research,91, 852–859.CrossRefPubMedGoogle Scholar