title: Chronic increase of urea leads to carbamylated proteins accumulation in tissues in a mouse model of CKD.
abstract: Carbamylation is a general process involved in protein molecular ageing due to the nonenzymatic binding of isocyanic acid, mainly generated by urea dissociation, to free amino groups. In vitro experiments and clinical studies have suggested the potential involvement of carbamylated proteins (CPs) in chronic kidney disease (CKD) complications like atherosclerosis, but their metabolic fate in vivo is still unknown. To address this issue, we evaluated protein carbamylation in the plasma and tissues of control and 75% nephrectomised C57BL/6J mice by LC-MS/MS assay of homocitrulline, the major carbamylation-derived product (CDP). A basal level of carbamylation was evidenced under all conditions, showing that carbamylation is a physiological process of protein modification in vivo. CP plasma concentrations increased in nephrectomized vs. control mice over the 20 weeks of the experiment (e.g. 335 ± 43 vs. 167 ± 19 μmol homocitrulline/mol lysine (p<0.001) 20 weeks after nephrectomy). Simultaneously, CP content increased roughly by two-fold in all tissues throughout the experiment. The progressive accumulation of CPs was specifically noted in long-lived extracellular matrix proteins, especially collagen (e.g. 1264 ± 123 vs. 726 ± 99 μmol homocitrulline/mol lysine (p<0.01) in the skin of nephrectomized vs. control mice after 20 weeks of evolution). These results show that chronic increase of urea, as seen in CKD, increases the carbamylation rate of plasma and tissue proteins. These results may be considered in the perspective of the deleterious effects of CPs demonstrated in vitro and of the correlation evidenced recently between plasma CPs and cardiovascular risk or mortality in CKD patients.
authors: Department of Pediatrics (Nephrology unit), University Hospital of Reims, Reims, France ; Laboratory of Biochemistry and Molecular Biology, FRE CNRS/URCA N° 3481, Faculty of Medicine, Reims, France.
authors: Christine
authors: C
authors: Pietrement
authors: Laëtitia
authors: L
authors: Gorisse
authors: Stéphane
authors: S
authors: Jaisson
authors: Philippe
authors: P
authors: Gillery
mesh_terms: D000818:Animals; D002219:Carbamates; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D007700:Kinetics; D051379:Mice; D009928:Organ Specificity; D011506:Proteins / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D014511:Uremia / Q000097:blood*
chemical_list: D002219:Carbamates; D011506:Proteins; D003094:Collagen