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

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

doi:10.1016/j.kint.2021.10.018

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

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

^*Corresponding author for this work

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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 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 language	English
Book series	Kidney International
Volume	101
Issue	3
Pages (from-to)	574-584
ISSN	0085-2538
DOIs	https://doi.org/10.1016/j.kint.2021.10.018
Publication status	Published - Mar 2022

Keywords

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

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10.1016/j.kint.2021.10.018Licence: CC BY

1-s2.0-S0085253821010346-mainFinal published version, 2.82 MBLicence: CC BY

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Jankowski, V., Saritas, T., Kjolby, M., Hermann, J., Speer, T., Himmelsbach, A., Mahr, K., Heuschkel, M. A., Schunk, S. J., Thirup, S., Winther, S., Bottcher, M., Nyegard, M., Nykjaer, A., Kramann, R., Kaesler, N., Jankowski, J., Floege, J., Marx, N., & Goettsch, C. (2022). Carbamylated sortilin associates with cardiovascular calcification in patients with chronic kidney disease. Kidney International, 101(3), 574-584. https://doi.org/10.1016/j.kint.2021.10.018

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title = "Carbamylated sortilin associates with cardiovascular calcification in patients with chronic kidney disease",

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 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.",

keywords = "carbamylation, cardiovascular calcification, cardiovascular disease, chronic kidney disease, post-translational modification, sortilin",

author = "Vera Jankowski and Turgay Saritas and Mads Kjolby and Juliane Hermann and Thimoteus Speer and Anika Himmelsbach and Kerstin Mahr and Heuschkel, {Marina Augusto} and Schunk, {Stefan J.} and Soren Thirup and Simon Winther and Morten Bottcher and Mette Nyegard and Anders Nykjaer and Rafael Kramann and Nadine Kaesler and Joachim Jankowski and Juergen Floege and Nikolaus Marx and Claudia Goettsch",

year = "2022",

month = mar,

doi = "10.1016/j.kint.2021.10.018",

language = "English",

volume = "101",

pages = "574--584",

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Jankowski, V, Saritas, T, Kjolby, M, Hermann, J, Speer, T, Himmelsbach, A, Mahr, K, Heuschkel, MA, Schunk, SJ, Thirup, S , Winther, S , Bottcher, M, Nyegard, M, Nykjaer, A, Kramann, R, Kaesler, N, Jankowski, J, Floege, J, Marx, N & Goettsch, C 2022, 'Carbamylated sortilin associates with cardiovascular calcification in patients with chronic kidney disease', Kidney International, vol. 101, no. 3, pp. 574-584. https://doi.org/10.1016/j.kint.2021.10.018

Carbamylated sortilin associates with cardiovascular calcification in patients with chronic kidney disease. / Jankowski, Vera; Saritas, Turgay; Kjolby, Mads et al.
In: Kidney International, Vol. 101, No. 3, 03.2022, p. 574-584.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Carbamylated sortilin associates with cardiovascular calcification in patients with chronic kidney disease

AU - Jankowski, Vera

AU - Saritas, Turgay

AU - Kjolby, Mads

AU - Hermann, Juliane

AU - Speer, Thimoteus

AU - Himmelsbach, Anika

AU - Mahr, Kerstin

AU - Heuschkel, Marina Augusto

AU - Schunk, Stefan J.

AU - Thirup, Soren

AU - Winther, Simon

AU - Bottcher, Morten

AU - Nyegard, Mette

AU - Nykjaer, Anders

AU - Kramann, Rafael

AU - Kaesler, Nadine

AU - Jankowski, Joachim

AU - Floege, Juergen

AU - Marx, Nikolaus

AU - Goettsch, Claudia

PY - 2022/3

Y1 - 2022/3

N2 - 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.

AB - 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.

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KW - cardiovascular calcification

KW - cardiovascular disease

KW - chronic kidney disease

KW - post-translational modification

KW - sortilin

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DO - 10.1016/j.kint.2021.10.018

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JF - Kidney International

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

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