MO453: Post-Translational Guanidinylation of Apolipoprotein C3 (APOC3) is Associated With Kidney and Vascular Injury

Abstract

Abstract BACKGROUND AND AIMS Cardiovascular diseases (CVD) and chronic kidney diseases (CKD) are highly prevalent in Western populations and account for a substantial proportion of mortality. We recently found that apolipoprotein C-3 (ApoC3), a constituent of triglyceride-rich lipoproteins, induces alternative NLRP3 inflammasome activation leading to sterile inflammation. In the present study, we aimed to assess post-translational modifications (PTMs) of ApoC3 in patients with CKD, to determine the effects of post-translationally modified ApoC3 in vitro and in vivo, and to test the relevance in a prospective clinical trial. METHOD Using mass-spectrometry, we screened ApoC3 for PTMs We determined the effects of modified ApoC3 on monocyte inflammatory response in vitro and assessed its effects in humanized mice subjected to a vascular injury model and unilateral ureter ligation. Finally, we assessed the association of post-translationally modified ApoC3 and cardiovascular and renal events in a prospective clinical trial of 543 CKD patients. RESULTS We identified post-translational guanidinylation of ApoC3 (gApoC3) in patients with CKD, which augments the proinflammatory effects of ApoC3. Mechanistically, guanidine and urea induced guanidinylation of ApoC3. gApoC3 accumulates in kidneys and plasma of mice subjected to a CKD model as determined by 2D-proteomic analyses. In humanized mice, gApoC3 promotes kidney fibrosis and impedes vascular regeneration. In the clinical trial, higher gApoC3 blood levels as determined by mass spectrometry were associated with increased mortality as well as cardiovascular and renal events. CONCLUSION Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, rendering gApoC3 a potential therapeutic target.