Prevention of chronic renal allograft rejection in rats with an oral endothelin A receptor antagonist

Background, Chronic rejection is the most common cause of graft loss in ren al transplantation, The pathomechanisms underlying chronic rejection are po orly understood, and no treatment has yet successfully been established. We hypothesized that, in analogy to models of reduced renal mass, the adminis tration of a selective endothelin (ET) A receptor antagonist could improve the course of chronic rejection in renal allografts. Methods. Experiments were performed in the Fisher-to-Lewis rat model of chr onic rejection, Lewis-->Lewis isografts served as controls. Animals were tr eated with either the oral selective ET-A receptor antagonist LU135252 (50 mg/kg/day) or vehicle. Animal survival, blood pressure, creatinine clearanc e, proteinuria, and urinary ET excretion were investigated for 24 weeks. Ki dneys were removed for light microscopical evaluation, determination of ET mRNA expression and tissue protein concentration, and immunohistochemical a ssessment of cell surface markers. Results. Rats with chronic rejection showed an increase in renal ET mRNA sy nthesis and ET protein content, Treatment with LU135252 resulted in a signi ficant improvement in survival after 24 weeks (0.92 vs. 0,38, P<0,01 by log -rank test). Creatinine clearance was higher in animals treated with the se lective ET-A receptor antagonist (P<0.05). LU135252 had no influence on blo od pressure and proteinuria, Selective ET-A blockade was associated with si gnificantly less morphological changes and a significant reduction of expre ssion of cell surface markers for macrophages (ED1), T cells (R73), and MHC II (F17-23-2), Conclusion. The renal ET-A system plays an important role in the pathomecha nisms underlying chronic renal allograft rejection, because the treatment w ith a selective ET-A receptor antagonist dramatically improves the course o f chronic renal failure after allograft transplantation. These results offe r a novel therapeutical option for treatment of chronic renal allograft rej ection, for which so far no therapy is known.