Lipocalin-2 and its variants

Abstract

Lipocalin-2 is a proinflammation adipokine, which is characterized by highly diversified expression and structure-function relationship. Due to the dynamic ligand-binding, protein-protein interaction and posttranslational modification, lipocalin-2 exists as variety variants, which differ in blood circulation or are expressed in tissues and organs. This study used specific immunoassay methods to measure and compare lipocalin-2 variants, including hLcn2, C87A and R81E, in human samples from healthy individuals and patients with cardiovascular (CVD) and/or chronic kidney (CKD) disease. Lipocalin-2 variants including hLcn2, C87A and R81E exist in different concentrations, but are significantly correlated with each other in plasma, serum and urine samples of healthy subjects. Serum C87A is correlated with parameters related to cardiac metabolism and renal function, while urinary R81E is mainly correlated with renal injury markers in healthy subjects. The potential of using different lipocalin-2 variants to stratify patients with CVD and/or CKD was evaluated. In CKD patients, both C87A and R81E were positively correlated with markers of renal tubular injury, but negtively correlated with eGFR. The urine levels of R81E gradually increases with the progress of the CKD stage. In CVD patients, although the majority (86.3%) exhibited heart failure with preserved ejection fraction (HFpEF), the plasma concentrations of C87A were significantly higher than those of the healthy subjects, and positively correlated with NT-proBNP, neutrophil activation markers and LVEF. Experiment were performed in mouse models with high fat diet (HFD)-induced obesity or aldosterone-induced cardiorenal injuries to assess the therapeutic potential of antibodies targeting hLcn2, C87A or R81E. Treatment with anti-C87A exerts beneficial effects on metabolic functions in mice fed with HFD, and has a protective effect on aldosterone-induced cardiac injury. Treatment with anti-R81E exhibits effective renal protection. Mouse lipocalin-2 is expressed in adipose progenitor cell subset which is characterized by Lin-PDGFα+Sca1+PDPN+CD29+ and CD9high. HFD treatment significantly increased the number of cells with PDGFα+Sca1+PDPN+CD29+mLcn2+ in SVF (stromal vascular fraction) from epididymal adipose tissue. In conclusion, the present study demonstrated that the lipocalin-2 variants represent useful biomarkers and potential drug targets for obesity-associated metabolic, CKD and CVD.