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

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)-[beta]1, 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.sup.b]) mice were transplanted to bilaterally nephrectomized BALB/c ([H-2.sup.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 [+ or -] 6 vs. 94 [+ or -] 39 [micro]M creatinine (P = 0.0015) and 22 [+ or -] 8 vs. 56 [+ or -] 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[beta]1 levels in grafts. Also, CI-1040 potently suppressed not only TGF[beta] 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-[beta]1