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This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/F672    most recent 90285.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wang, S. Articles by Du, C. Search for Related Content PubMed PubMed Citation Articles by Wang, S. Articles by Du, C.

Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling

¹Departments of Medicine, Microbiology, and Immunology and ²Department of Surgery, University of Western Ontario; ³The Multi-Organ Transplant Program, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario; and ⁴Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada

Submitted 30 April 2008 ; accepted in final form 1 July 2008

Chronic allograft nephropathy (CAN), the most common cause of late kidney allograft failure, is not effectively prevented by immunosuppressive regimens. Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) via MEK mediates actions of various growth factors, including transforming growth factor (TGF)-β1, which plays a key role in CAN. Hence, we tested the therapeutic potential of MEK-ERK1/2 signaling disruption to prevent CAN. Kidneys from C57BL/6J (H-2^b) mice were transplanted to bilaterally nephrectomized BALB/c (H-2^d) mice. At 14 days after transplantation, the recipients were subjected to 28 days of treatment with the MEK inhibitor CI-1040. All six CI-1040-treated allografts survived, while two of seven grafts in the vehicle-treated group were lost. At the end of the experiment, the function and structure of grafts in the CI-1040-treated group were significantly preserved, as indicated by lower levels of serum creatinine or blood urea nitrogen than in the vehicle-treated group [30 ± 6 vs. 94 ± 39 µM creatinine (P = 0.0015) and 22 ± 8 vs. 56 ± 25 mM BUN (P = 0.0054)] and reduced CAN in the CI-1040-treated group compared with vehicle controls (CAN score = 4.2 vs. 10.3, P = 0.0119). The beneficial effects induced by CI-1040 were associated with reduction of ERK1/2 phosphorylation and TGFβ1 levels in grafts. Also, CI-1040 potently suppressed not only TGFβ biosynthesis in kidney cell cultures but also antiallograft immune responses in vitro and in vivo. Our data suggest that interference of MEK-ERK1/2 signaling with a pharmacological agent (e.g., CI-1040) has therapeutic potential to prevent CAN in kidney transplantation.

kidney transplantation; experimental therapy; transforming growth factor-β1