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)-beta1, 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 microM 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 TGFbeta1 levels in grafts. Also, CI-1040 potently suppressed not only TGFbeta 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.
Wang
Shuang
S
Department of Urologic Sciences, University of British Columbia, Jack Bell Research Centre, 2660 Oak Street, Vancouver, BC, Canada.
Jiang
Jifu
J
Guan
Qiunong
Q
Wang
Hao
H
Nguan
Christopher Y C
CY
Jevnikar
Anthony M
AM
Du
Caigan
C
D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006084:Graft Rejection / Q000188:drug therapy* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D007166:Immunosuppressive Agents; D053773:Transforming Growth Factor beta1; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse