Neutrophil Gelatinase–Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 66; no. 1; pp. 158 - 166
• Main Authors: Tarjus, Antoine, Martínez-Martínez, Ernesto, Amador, Cristian, Latouche, Céline, El Moghrabi, Soumaya, Berger, Thorsten, Mak, Tak W., Fay, Renaud, Farman, Nicolette, Rossignol, Patrick, Zannad, Faiez, López-Andrés, Natalia, Jaisser, Frédéric
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.07.2015; American Heart Association
• Subjects: Acute-Phase Proteins; Acute-Phase Proteins - deficiency; Acute-Phase Proteins - genetics; Acute-Phase Proteins - pharmacology; Acute-Phase Proteins - physiology; Aldosterone; Aldosterone - blood; Aldosterone - toxicity; Animals; Aorta; Aorta - drug effects; Aorta - pathology; Cardiology and cardiovascular system; Cardiomyopathy, Hypertrophic; Cardiomyopathy, Hypertrophic - chemically induced; Cardiomyopathy, Hypertrophic - physiopathology; Cells, Cultured; Cytokines; Cytokines - biosynthesis; Cytokines - genetics; Female; Fibroblasts; Fibrosis; Galectin 3; Galectin 3 - biosynthesis; Galectin 3 - blood; Galectin 3 - genetics; Human health and pathology; Humans; Hypertension; Hypertension - physiopathology; Hypertrophy; Kidney; Kidney - pathology; Life Sciences; Lipocalin-2; Lipocalins; Lipocalins - blood; Lipocalins - genetics; Lipocalins - pharmacology; Lipocalins - physiology; Male; Mice; Myocardium; Myocardium - cytology; Myocardium - metabolism; Myocytes, Smooth Muscle; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - physiology; Nephrectomy; Nephrectomy - adverse effects; Obesity, Abdominal; Obesity, Abdominal - blood; Obesity, Abdominal - physiopathology; Oncogene Proteins; Oncogene Proteins - deficiency; Oncogene Proteins - genetics; Oncogene Proteins - physiology; Peptide Fragments; Peptide Fragments - blood; Procollagen; Procollagen - blood; Proto-Oncogene Proteins; Proto-Oncogene Proteins - blood; Proto-Oncogene Proteins - pharmacology; Proto-Oncogene Proteins - physiology; Rats; Recombinant Proteins; Recombinant Proteins - pharmacology; collagen type I; lipocalin 2; fibroblast; mineralocorticoid receptor; aldosterone
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.115.05431

Activation of the mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs). We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase–associated lipocalin (NGAL), is a primary target of aldosterone/mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of aldosterone/mineralocorticoid receptor profibrotic effects in the cardiovascular system. Correlations between aldosterone and profibrotic markers, such as procollagen type I N-terminal peptide, were investigated in healthy subjects and subjects with abdominal obesity. The implication of Lcn2 in the mineralocorticoid pathway was studied using Lcn2 knockout mice subjected to a nephrectomy/aldosterone/salt (NAS) challenge for 4 weeks. In human subjects, NGAL/matrix metalloproteinase 9 was positively correlated with plasma aldosterone and fibrosis biomarkers. In mice, loss of Lcn2 prevented the NAS-induced increase of plasma procollagen type I N-terminal peptide, as well as the increase of collagen fibers deposition and collagen I expression in the coronary vessels and the aorta. The lack of Lcn2 also blunted the NAS-induced increase in systolic blood pressure. Ex vivo, treatment of human fibroblasts with recombinant Lcn2 induced the expression of collagen I and the profibrotic galectin-3 and cardiotrophin-1 molecules. Our results showed that Lcn2 plays a key role in aldosterone/mineralocorticoid receptor–mediated vascular fibrosis. The clinical data indicate that this may translate in human patients. Lcn2 is, therefore, a new biotarget in cardiovascular fibrosis induced by mineralocorticoid activation.