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Lipocalin‐2 variants as biomarkers and drug targets for cardiovascular and renal diseases

Lipocalin‐2 is a proinflammatory adipokine implicated in metabolic, cardiovascular and renal diseases. This molecule exists as multiple variants in human biofluid and tissue samples. The present study evaluated the molecular features of different lipocalin‐2 variants, including hLcn2, C87A and R81E, and their application as biomarkers and drug targets for cardiovascular (CVD) or chronic kidney (CKD) diseases. The results demonstrate that in patients with CKD, the urine levels of C87A and R81E were higher and positively correlated with the tubular injury markers. With increasing severity of CKD, there was a progressive elevation of the urine R81E levels. In patients with CVD, the plasma levels of C87A were significantly increased and positively correlated with N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), neutrophil activation markers and left ventricular ejection fraction (LVEF), independent of age, gender, smoking and body mass index (BMI). In mice subjected to a six‐week treatment with aldosterone and high salt after uninephrectomy, treatment with antibody against C87A significantly attenuated diastolic dysfunction and cardiac injuries, whereas treatment with antibody against R81E elicited more potent protective effects on renal injuries. In conclusion, simultaneouslyquantifying differentlipocalin‐2 variants is useful for risk assessment and management of patients with CKD and/or CVD. Targeting the pathological forms of lipocalin‐2 represents a novel and promising strategy for therapeutic interventions.