Carbamylated proteins activate glomerular mesangial cells and stimulate collagen deposition

Carbamylated proteins formed in renal insufficiency from the spontaneous de composition of urea exert a variety of metabolic effects, Here we examined the effects of carbamylated proteins on glomerular mesangial cells to deter mine whether urea retention in early renal insufficiency may itself promote glomerular sclerosis and hasten the progression to kidney failure. To this effect we carbamylated fetal bovine serum proteins in vitro and tested the ir effect on mesangial cell proliferation (by tritiated thymidine uptake), de novo protein synthesis (by tritiated leucine uptake), collagen I and col lagen IV accumulation (by avidin-biotin enzyme immunoassay), and gelatinase levels in the medium (by zymography and quantitative fluorescence assay), Carbamylated fetal bovine serum at concentrations present in uremia increas ed tritiated thymidine incorporation by 50% without altering tritiated leuc ine incorporation, and it increased collagens I and IV in the monolayer by 150% to 300%. Gelatinase activity was unchanged, We conclude that carbamyla ted proteins can activate mesangial cells to a profibrogenic phenotype, Fro m a clinical perspective, the carbamylation of proteins by elevated urea le vels may accelerate the progression to kidney failure and thus set up a vic ious cycle in which the nitrogen retention itself would cause further progr ession of fibrosis and deterioration of kidney function.