Guanidinylation compromises the anti-inflammatory and anti-oxidative properties of apolipoprotein A-I in chronic kidney disease progression.

Abstract

Chronic kidney disease (CKD) substantially heightens the likelihood of cardiovascular events, in part due to the impaired functionality of high-density lipoprotein (HDL) and its connection with atherosclerosis. Here, 82 patients with CKD stages 2-5 had their plasma isolated and analyzed using mass spectrometry to detect post-translational modifications of apolipoprotein A-I (apoA-I), the main protein component of HDL. Guanidinylation, a non-enzymatic post-translational modification, led to increased levels of apoA-I with CKD progression. The increase in guanidinylated apoA-I became significant from CKD stage 3 onwards. The modification patterns of apoA-I in patients with CKD were mimicked in vitro by exposure to O-methylisourea bisulfate. The thus modified apoA-I was used for functional assays which revealed that guanidinylation compromised the anti-inflammatory and anti-oxidative properties of apoA-I,of potential relevance for clinical findings. Specifically, guanidinylated apoA-I activated inflammatory kinases in macrophages, suggesting a mechanistic link between apoA-I modifications and inflammatory responses. These findings are in favor of alterations in the functional properties of apoA-I in patients with CKD due to guanidinylation. The identification of high guanidinylated apoA-I peptide levels in plasma highlights a novel aspect of protein modification in CKD pathophysiology. The results of our study may provide a better understanding of the molecular mechanisms underlying CKD-related cardiovascular complications and highlight the importance and the need to minimize post-translational modifications in patients with CKD.