Lipocalin-2 Ameliorates CKD-Associated Vascular Calcification Through Promoting Fatty Acid β Oxidation

Background: Vascular calcification (VC) is common in chronic kidney disease (CKD) patients, driven primarily by osteogenic transformation of vascular smooth muscle cells (VSMCs). Lipocalin-2 (LCN2), a secreted protein implicated in atherosclerosis and abdominal aortic aneurysm, but its role and mechanism in CKD-associated VC remains unclear. Methods: The effects of LCN2 on vascular calcification were explored in vitro and in vivo. Transcriptome sequencing, proteomics, co-immunoprecipitation mass spectrum and molecular docking were performed to investigate the mechanism by which LCN2 plays a role in VC. Results: LCN2 was downregulated in CKD patients with VC and high-phosphorus-treated VSMCs. Recombinant LCN2 reduced calcification and osteogenic differentiation in VSMCs, while LCN2 knockdown worsened it. In CKD mice, AAV-mediated LCN2 overexpression alleviated aortic calcification. Multi-omics revealed LCN2 activates fatty acid β-oxidation by binding with very long-chain acyl-CoA dehydrogenase (Acadvl). Acadvl knockdown exacerbated calcification and diminished LCN2's protective effects. Conclusion: LCN2 interacts with Acadvl and then enhances fatty acid β-oxidation, thus ameliorating CKD-associated VC, which offers a novel therapeutic target against VC. Funding: Government Support – Non-U.S.Figure 1. Overexpression of LCN2 improved aortic vascular calcification and inhibited osteogenic differentiation in mice.