Submitted on April 30, 2008
Revised on June 10, 2008
Accepted on July 1, 2008
Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinases1/2 signaling
Shuang Wang1, Jifu Jiang1, Qiunong Guan2, Hao Wang1, Christopher Y.C. Nguan2, Anthony Micheal Jevnikar3, and Caigan Du2*
1 The University of Western Ontario
2 The University of British Columbia
3 University of Western Ontario
* To whom correspondence should be addressed. E-mail: caigan{at}interchange.ubc.ca.
Chronic allograft nephropathy (CAN) is the most common cause of late kidney allograft failure, and is not effectively prevented by the current immunosuppressive regimens. Activation of extracellular signal-regulated kinases 1/2 (ERK1/2) via MEK mediates actions of various growth factors including TGF-
1, which plays a key role in CAN. Hence, the therapeutic potential of disruption of MEK-ERK1/2 signaling to prevent CAN was tested. Kidneys from C57BL/6J mice (H-2b) were transplanted to bilaterally nephrectomized Balb/c mice (H-2d). The recipients were treated with MEK inhibitor CI-1040 for 28 days after 14 days post-transplantation. All six allografts receiving CI-1040 treatment survived, while two of seven grafts were lost in vehicle group. At the end of the experiment, the function and structure of grafts in CI-1040 treated recipients was significantly preserved, indicated by lower levels of serum creatinine or blood urea nitrogen (BUN) compared to those in vehicle group (creatinine: 30±6 µM vs. 94±39 µM, P=0.0015; BUN: 22±8 mM vs. 56±25 mM, P=0.0054), and reduced CAN in CI-1040-treated group as compared to that in vehicle controls (CAN score: 4.2 vs. 10.3, P=0.0119). CI-1040 beneficial effects were associated with reduction of phosphorylation of ERK1/2 and TGF-1 levels in grafts. Also CI-1040 potently suppressed not only TGF-1 biosynthesis in kidney cell cultures but also anti-allograft immune responses in vitro and in vivo. Our data suggest that interference of MEK-ERK1/2 signaling with pharmacological agent (e.g. CI-1040) has therapeutic potential to prevent CAN in kidney transplantation.
