Abstract
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 invitro carbamylated sortilin. Further, carbamylated sortilin increased vascular calcification invitro and exvivo 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.
Highlights
Sortilin, an intracellular sorting receptor, has been identified as a cardiovascular risk factor in the general population
Sortilin carbamylation is associated with vascular calcification in chronic kidney disease (CKD) patients On the basis of our data that carbamylated sortilin residues were found to associate with CKD and calcification, we studied CKD participants of the Cardiovascular In Depth Assessment (CARVIDA) study, in whom computed tomographic scans quantified CAC
In various experimental in vitro and in vivo studies and 2 independent prospective cohorts, we demonstrate that patients with CKD exhibit a specific pattern of posttranslational carbamylated sortilin lysine residues in the circulation, which can be detected in the vascular wall
Summary
An intracellular sorting receptor, has been identified as a cardiovascular risk factor in the general population. A bout 1 in 10 people worldwide experience chronic kidney disease (CKD).[1] Impaired kidney function is a major independent risk factor for cardiovascular (CV) morbidity and mortality and all-cause mortality.[1,2] patients with CKD are much more likely to die from CV events than to develop dialysis-requiring kidney failure.[3] The excess calcific mineral deposition within vascular tissue observed in CKD patients contributes mainly to the increased CV risk.[4] CKD facilitates post-translational modification (PTM) of proteins.[5] PTMs, in turn, have been linked to CV calcification,[6] suggesting that a better understanding of PTMs in CKD-induced calcification processes could reveal novel. Achieving a better understanding of the mechanistic relationship between circulating sortilin and the regulatory impact of PTM in CKD will broaden the knowledge of sortilin in CV calcification
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