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.

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.

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.

Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target.

并存的 CKD 和心血管疾病在西方人群中非常普遍，并导致大量死亡率。我们最近发现载脂蛋白 C-3 (ApoC3) 是富含甘油三酯的脂蛋白的主要成分，它通过替代途径激活人单核细胞中的 NOD 样受体蛋白 3 (NLRP3) 炎性体，从而诱导无菌性全身炎症。

为了识别 CKD 患者 ApoC3 的翻译后修饰，我们使用质谱分析这些患者和健康个体的 ApoC3。我们确定了翻译后修饰的 ApoC3 对体外单核细胞炎症反应的影响，以及对接受单侧输尿管结扎的人源化小鼠（肾纤维化模型）和血管损伤和再生的人源化小鼠模型的影响。最后，我们对 543 名 CKD 患者进行了一项前瞻性观察试验，以探讨翻译后修饰的 ApoC3 与这些患者的肾脏和心血管事件的关联。

我们在 CKD 患者中发现了显着的 ApoC3 (gApoC3) 翻译后胍基化。我们还发现，从机制上讲，胍和尿素会诱导 ApoC3 的胍基化。二维蛋白质组学分析表明，在 CKD 小鼠模型（喂食富含腺嘌呤的饮食的小鼠）中，gApoC3 在肾脏和血浆中积累。此外，gApoC3在体外增强了 ApoC3 在单核细胞中的促炎作用。在人源化小鼠中，gApoC3 促进肾组织纤维化并阻碍血管再生。在 CKD 患者中，较高的 gApoC3 血浆水平（通过质谱测定）与死亡率增加以及肾脏和心血管事件相关。

ApoC3 的胍基化代表了 CKD 和 CKD 相关血管损伤的一种新的致病机制，表明 gApoC3 是一个潜在的治疗靶点。