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Carbamylated sortilin associates with cardiovascular calcification in patients with chronic kidney disease

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  • Vera Jankowski, RWTH Aachen University
  • ,
  • Turgay Saritas, RWTH Aachen University
  • ,
  • Mads Kjolby
  • Juliane Hermann, RWTH Aachen University
  • ,
  • Thimoteus Speer, Saarland University
  • ,
  • Anika Himmelsbach, RWTH Aachen University
  • ,
  • Kerstin Mahr, RWTH Aachen University
  • ,
  • Marina Augusto Heuschkel, RWTH Aachen University
  • ,
  • Stefan J. Schunk, Saarland University
  • ,
  • Soren Thirup
  • Simon Winther
  • Morten Bottcher
  • Mette Nyegard, Aalborg University
  • ,
  • Anders Nykjaer
  • Rafael Kramann, RWTH Aachen University
  • ,
  • Nadine Kaesler, RWTH Aachen University
  • ,
  • Joachim Jankowski, RWTH Aachen University
  • ,
  • Juergen Floege, RWTH Aachen University
  • ,
  • Nikolaus Marx, RWTH Aachen University
  • ,
  • Claudia Goettsch, RWTH Aachen University

Sortilin, an intracellular sorting receptor, has been identified as a cardiovascular risk factor in the general population. Patients with chronic kidney disease (CKD) are highly susceptible to develop cardiovascular complications such as calcification. However, specific CKD-induced posttranslational protein modifications of sortilin and their link to cardiovascular calcification remain unknown. To investigate this, we examined two independent CKD cohorts for carbamylation of circulating sortilin and detected increased carbamylated sortilin lysine residues in the extracellular domain of sortilin with kidney function decline using targeted mass spectrometry. Structure analysis predicted altered ligand binding by carbamylated sortilin, which was verified by binding studies using surface plasmon resonance measurement, showing an increased affinity of interleukin 6 to in vitro carbamylated sortilin. Further, carbamylated sortilin increased vascular calcification in vitro and ex vivo that was accelerated by interleukin 6. Imaging by mass spectrometry of human calcified arteries revealed in situ carbamylated sortilin. In patients with CKD, sortilin carbamylation was associated with coronary artery calcification, independent of age and kidney function. Moreover, patients with carbamylated sortilin displayed significantly faster progression of coronary artery calcification than patients without sortilin carbamylation. Thus, carbamylated sortilin may be a risk factor for cardiovascular calcification and may contribute to elevated cardiovascular complications in patients with CKD.

Original languageEnglish
Book seriesKidney International
Pages (from-to)574-584
Publication statusPublished - Mar 2022

    Research areas

  • carbamylation, cardiovascular calcification, cardiovascular disease, chronic kidney disease, post-translational modification, sortilin

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