TY - JOUR
T1 - Guanidinylated apolipoprotein C3 (ApoC3) associates with kidney and vascular injury
AU - Schunk, Stefan J.
AU - Hermann, Juliane
AU - Sarakpi, Tamim
AU - Triem, Sarah
AU - Lellig, Michaela
AU - Hahm, Eunsil
AU - Zewinger, Stephen
AU - Schmit, David
AU - Becker, Ellen
AU - Mollmann, Julia
AU - Lehrke, Michael
AU - Kramann, Rafael
AU - Boor, Peter
AU - Lipp, Peter
AU - Laufs, Ulrich
AU - Marz, Winfried
AU - Reiser, Jochen
AU - Jankowski, Joachim
AU - Fliser, Danilo
AU - Speer, Thimoteus
AU - Jankowski, Vera
N1 - Publisher Copyright:
© 2021 American Society of Nephrology. All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - Background Coexistent CKD and cardiovascular diseases are highly prevalent inWestern populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway. Methods To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response in vitro, as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients. Results We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 in monocytes in vitro. In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events. Conclusions Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKDassociated vascular injury, pointing to gApoC3 as a potential therapeutic target.
AB - Background Coexistent CKD and cardiovascular diseases are highly prevalent inWestern populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway. Methods To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response in vitro, as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients. Results We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 in monocytes in vitro. In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events. Conclusions Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKDassociated vascular injury, pointing to gApoC3 as a potential therapeutic target.
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U2 - 10.1681/ASN.2021040503
DO - 10.1681/ASN.2021040503
M3 - Article
C2 - 34588185
AN - SCOPUS:85120683640
SN - 1046-6673
VL - 32
SP - 1
EP - 15
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -