BACKGROUND: 4SC-101 is a novel dihydroorotate dehydrogenase inhibitor and a blocker of interleukin (IL)-17 secretion with beneficial effects in experimental lupus and inflammatory bowel disease. Its immunomodulatory effect on acute kidney rejection is not known; therefore, in this study, the impact of 4SC-101 was examined in a rat model of acute kidney rejection. METHODS: The kidneys of Brown-Norway rats were orthotopically transplanted into bilaterally nephrectomized Lewis recipients. Allograft recipients were administered with 4SC-101 at dosages of 4, 20, or 60 mg/kg per day, and survival was assessed. In the second setting, the animals were harvested 3 or 5 days after transplantation (Tx), and graft histologic diagnosis was determined. The effects of 4SC-101 on impaired renal function were examined in a model of 5/6 nephrectomy in Lewis rats. RESULTS: The recipients treated with 20-mg/kg 4SC-101 showed prolonged survival compared with placebo-treated animals (mean±SEM, 24±9.3 vs. 5.4±3 days), paralleled by less severe histologic features of acute kidney rejection such as interstitial/perivascular infiltration and tubulitis 3 and 5 days after Tx, and a lower level of IL-17 messenger RNA 5 days after Tx compared with the placebo-treated animals. In the 5/6 nephrectomy model, 20-mg/kg 4SC-101 reduced proteinuria, glomerulosclerosis, and fibrosis with decreased IL-17 messenger RNA expression. CONCLUSIONS: 4SC-101 prolongs survival after Tx, paralleled by amelioration of histologic signs of acute rejection. Furthermore, it showed no worsening effects on kidney function in a remnant kidney model and even slowed the progression of proteinuria and kidney fibrosis. Therefore, 4SC-101 might be a promising pharmaceutical agent in Tx medicine for further investigations.
BACKGROUND:4SC-101 is a novel dihydroorotate dehydrogenase inhibitor and a blocker of interleukin (IL)-17 secretion with beneficial effects in experimental lupus and inflammatory bowel disease. Its immunomodulatory effect on acute kidney rejection is not known; therefore, in this study, the impact of 4SC-101 was examined in a rat model of acute kidney rejection. METHODS: The kidneys of Brown-Norway rats were orthotopically transplanted into bilaterally nephrectomized Lewis recipients. Allograft recipients were administered with 4SC-101 at dosages of 4, 20, or 60 mg/kg per day, and survival was assessed. In the second setting, the animals were harvested 3 or 5 days after transplantation (Tx), and graft histologic diagnosis was determined. The effects of 4SC-101 on impaired renal function were examined in a model of 5/6 nephrectomy in Lewis rats. RESULTS: The recipients treated with 20-mg/kg 4SC-101 showed prolonged survival compared with placebo-treated animals (mean±SEM, 24±9.3 vs. 5.4±3 days), paralleled by less severe histologic features of acute kidney rejection such as interstitial/perivascular infiltration and tubulitis 3 and 5 days after Tx, and a lower level of IL-17 messenger RNA 5 days after Tx compared with the placebo-treated animals. In the 5/6 nephrectomy model, 20-mg/kg 4SC-101 reduced proteinuria, glomerulosclerosis, and fibrosis with decreased IL-17 messenger RNA expression. CONCLUSIONS:4SC-101 prolongs survival after Tx, paralleled by amelioration of histologic signs of acute rejection. Furthermore, it showed no worsening effects on kidney function in a remnant kidney model and even slowed the progression of proteinuria and kidney fibrosis. Therefore, 4SC-101 might be a promising pharmaceutical agent in Tx medicine for further investigations.
Authors: Marianne Lucas-Hourani; Hélène Munier-Lehmann; Farah El Mazouni; Nicholas A Malmquist; Jane Harpon; Eloi P Coutant; Sandrine Guillou; Olivier Helynck; Anne Noel; Artur Scherf; Margaret A Phillips; Frédéric Tangy; Pierre-Olivier Vidalain; Yves L Janin Journal: J Med Chem Date: 2015-06-30 Impact factor: 7.446