Guanidinylated Apolipoprotein C3 (ApoC3) Associates with Kidney and Vascular Injury.

Abstract

BACKGROUND:

Coexistent CKD and cardiovascular diseases are highly prevalent in Western 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 CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target.

• Authors: Stefan J Schunk, Juliane Hermann, Tamim Sarakpi, Sarah Triem, Michaela Lellig, Eunsil Hahm, Stephen Zewinger, David Schmit, Ellen Becker, Julia Möllmann, Michael Lehrke, Rafael Kramann, Peter Boor, Peter Lipp, Ulrich Laufs, Winfried März, Jochen Reiser, Joachim Jankowski, Danilo Fliser, Thimoteus Speer, Vera Jankowski
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 32 Issue 12 Pg. 3146-3160 (12 01 2021) ISSN: 1533-3450 [Electronic] United States
• PMID: 34588185 (Publication Type: Observational Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by the American Society of Nephrology.

Chemical References

• Apolipoprotein C-III

Topics

• Humans
• Mice
• Animals
• Apolipoprotein C-III (metabolism)
• Vascular System Injuries
• Proteomics
• Cardiovascular Diseases
• Disease Models, Animal
• Kidney (metabolism)
• Renal Insufficiency, Chronic
• Fibrosis