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Mechanism of how carbamylation reduces albumin binding to FcRn contributing to increased vascular clearance.
Yadav, Shiv Pratap S; Sandoval, Ruben M; Zhao, Jingfu; Huang, Yifan; Wang, Exing; Kumar, Sudhanshu; Campos-Bilderback, Silvia B; Rhodes, George; Mechref, Yehia; Molitoris, Bruce A; Wagner, Mark C.
Afiliação
  • Yadav SPS; Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
  • Sandoval RM; Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
  • Zhao J; Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas.
  • Huang Y; Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas.
  • Wang E; Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, Texas.
  • Kumar S; Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
  • Campos-Bilderback SB; Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
  • Rhodes G; Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
  • Mechref Y; Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas.
  • Molitoris BA; Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
  • Wagner MC; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana.
Am J Physiol Renal Physiol ; 320(1): F114-F129, 2021 01 01.
Article em En | MEDLINE | ID: mdl-33283642
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 two-photon imaging of the Munich Wistar Frömter (MWF) rat kidney and liver allowed us to characterize filtration and proximal tubule uptake 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 rat serum albumin (cRSA) and altered distribution of cRSA in both the kidney and liver at 16 h post intravenous injection. By evaluating the time course of carbamylation and associated charge, size, shape, and binding parameters in combination with in silico analysis and mass spectrometry, the critical binding interaction impacting carbamylated albumin's reduced FcRn binding was identified as K524. Carbamylation of RSA had no effect on glomerular filtration or proximal tubule uptake. These data indicate urea-mediated time-dependent carbamylation of albumin lysine K524 resulted in reduced binding to CUB7,8 and FcRn that contribute to altered albumin transport, leading to increased vascular clearance and increased liver and endothelial tissue accumulation.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Albumina Sérica / Receptores Fc / Antígenos de Histocompatibilidade Classe I / Insuficiência Renal Crônica / Túbulos Renais Proximais / Fígado Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Am J Physiol Renal Physiol Assunto da revista: FISIOLOGIA / NEFROLOGIA Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Albumina Sérica / Receptores Fc / Antígenos de Histocompatibilidade Classe I / Insuficiência Renal Crônica / Túbulos Renais Proximais / Fígado Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Am J Physiol Renal Physiol Assunto da revista: FISIOLOGIA / NEFROLOGIA Ano de publicação: 2021 Tipo de documento: Article