Reduction in chronic allograft nephropathy by inhibition of p38 mitogen-activated protein kinase

Background: Chronic allograft nephropathy (CAN) is the major cause for late graft loss and is therefore a key target for therapy. Methods: The impact of p38 mitogen-activated kinase (MAPK) on CAN was investigated by administering FR167653 (32 mg/kg/day), a specific inhibitor of p38 MAPK, for 4 weeks in addition to conventional cyclosporine therapy (1.5 mg/kg/day for 5 days) in an established experimental rat transplantation model. Results: Transplanted rats develop glomerulosclerosis, arterial obliteration, interstitial fibrosis and tubular atrophy, all of which are characteristic of CAN, resulting in shortened survival on 32 weeks. However, the inhibition of p38 MAPK by daily subcutaneous treatment with FR167653 resulted in reduced CAN with preserved renal function and prolonged survival. The FR1167653-treated rats had fewer phosphorylated p38 MAPK-positive cells in treated kidneys. Concomitantly, the expression of monocyte chemoattractant protein-1/CCL2 and transforming growth factor-P, was markedly reduced. Conclusion: These results suggest that p38 MAPK phosphorylation is involved in the pathogenesis of CAN and provide evidence that p38 MAPK is a novel, appealing therapeutic target for combating CAN. Copyright (c) 2006 S. Karger AG, Basel.