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

Abstract

A ldosterone via the activation of the mineralocorticoid receptor (MR) is a main actor of renal sodium reabsorption and water homeostasis. Extra-renal effects of the mineralocorticoid pathway have now been characterized, especially in the cardiovascular system, opening on new dimensions of the aldosterone/MR pathway in physiology, pathophysiology, and diseases. In the cardiovascular system, mineralocorticoid signaling has been shown to play an important role in the progression of cardiovascular diseases (CVDs). Previous reports using transgenic mouse models or pharmacological approaches demonstrated adverse effects of aldosterone on cardiac remodeling and fibrosis, inflammation, and hypertension.1 These features are prevented by the pharmacological blockade of the MR. In humans, several clinical studies showed the beneficial effects of MR antagonism in addition to standard care, to reduce mortality and morbidity in patients with severe 2 or mild heart failure (HF) 3 or after acute myocardial infarction. 4 Understanding the molecular mechanisms of mineralocorticoid activation pathway in cardiovascular pathophysiology remains incomplete. Indeed, a better knowledge of the underlying mechanisms may highlight novel mediators of the MR signaling cascade. These newly identified intermediates could be good candidates as biotargets for novel pharmacological approaches, especially in diseases where the aldosterone/MR pathway is involved. Moreover, these biotargets may as well be considered as potent biomarkers of MR activation, Abstract-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. allowing a better selectio...

Nitric oxide–sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction

“…This finding was paralleled by a beneficial modulation of cardiac gene expression of fibronectin (Fn), connected tissue growth factor (Ctgf), and neutrophil gelatinase-associated lipocalin (Ngal). Ngal has been proposed as a biotarget for cardiovascular fibrosis (40). These results are consistent with other studies using NOsGC stimulators, showing a reduction in cardiac fibrosis in a blood pressure-independent manner (41,42).…”

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…Indeed, gene inactivation of CT1 (Lopez-Andres et al, 2011), Gal3 (Calvier et al, 2013;, and lipocalin 2 (Tarjus et al, 2015c) blunted the cardiac remodeling and inflammation induced by mineralocorticoids in experimental mouse models. These observations highlight the underlying essential role of NGAL in mineralocorticoid-mediated extracellular matrix remodeling (Leopold, 2015).…”

Vascular Mineralocorticoid Receptors

“…37 In humans, lipocalin-2 binds to and stabilizes matrix metalloproteinase 9, an important regulator of cardiac fibrosis. 38 Deletion of lipocalin-2 prevented the development of perivascular fibrosis in response to mineralocorticoid/salt in the heart and aorta of mice and reduces blood pressure. 38 In vitro stimulation of human fibroblasts with lipocalin-2 leads to an upregulation of different profibrotic genes, among others, galectin-3.…”

“…38 Deletion of lipocalin-2 prevented the development of perivascular fibrosis in response to mineralocorticoid/salt in the heart and aorta of mice and reduces blood pressure. 38 In vitro stimulation of human fibroblasts with lipocalin-2 leads to an upregulation of different profibrotic genes, among others, galectin-3. 38 Galectin-3 is a secreted protein that is involved in fibrosis, inflammation, and cell-cell interaction.…”

“…38 In vitro stimulation of human fibroblasts with lipocalin-2 leads to an upregulation of different profibrotic genes, among others, galectin-3. 38 Galectin-3 is a secreted protein that is involved in fibrosis, inflammation, and cell-cell interaction. Galectin-3 expression has been found to positively correlate with aortic pulse wave velocity in humans, 39 and it is upregulated in obese patients with left ventricular diastolic dysfunction.…”