Mechanism of How Carbamylation Reduces Albumin Binding to FcRn contributing to increased vascular clearance.

Mechanism of How Carbamylation Reduces Albumin Binding to FcRn contributing to increased vascular clearance. Am J Physiol Renal Physiol. 2020 Dec 07;: Authors: Yadav SPS, Sandoval R, Zhao J, Huang Y, Wang E, Kumar S, Campos-Bilderback SB, Rhodes GJ, Mechref Y, Molitoris BA, Wagner MC Abstract Chronic kidney disease results in high serum urea concentrations leading to excessive protein carbamylation, primarily albumin. This is associated with increased cardiovascular disease and mortality. Multiple methods were used to address whether carbamylation alters albumin metabolism. Intravital 2-photon imaging of the Munich Wistar Fromter (MWF) rat kidney and liver allowed us to characterize filtration and proximal tubule and liver uptake. Microscale thermophoresis enabled quantification of Cubilin (CUB7,8 domain) and FcRn binding. Finally, multiple biophysical methods including dynamic light scattering, Small-angle X-ray scattering, LC-MS/MS and in silico analyses were used to identify the critical structural alterations and amino acid modifications of rat albumin. Carbamylation of albumin reduced binding to CUB7,8 and FcRn in a dose-dependent fashion. Carbamylation markedly increased vascular clearance of carbamylated albumin (cRSA) and altered distribution of cRSA in both the kidney and liver at 16hrs post intravenous injection. By evaluating the time course of carbamylation and associated charge, size, shape and binding parameters in comb...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research