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Kidneys from C57BL\/6J (H-2<jats:sup>b<\/jats:sup>) mice were transplanted to bilaterally nephrectomized BALB\/c (H-2<jats:sup>d<\/jats:sup>) 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 \u00b1 6 vs. 94 \u00b1 39 \u03bcM creatinine ( P = 0.0015) and 22 \u00b1 8 vs. 56 \u00b1 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 TGF\u03b21 levels in grafts. Also, CI-1040 potently suppressed not only TGF\u03b2 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.<\/jats:p>","DOI":"10.1152\/ajprenal.90285.2008","type":"journal-article","created":{"date-parts":[[2008,7,10]],"date-time":"2008-07-10T00:44:41Z","timestamp":1215650681000},"page":"F672-F679","source":"Crossref","is-referenced-by-count":8,"title":["Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling"],"prefix":"10.1152","volume":"295","author":[{"given":"Shuang","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jifu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiunong","family":"Guan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher Y. 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