NGAL role in cardio-renal diseases

Clinical Science (2018) 132 909–923
https://doi.org/10.1042/CS20171592
Review Article
More than a simple biomarker: the role of NGAL in

cardiovascular and renal diseases
Mathieu Buonafine1 , Ernesto Martinez-Martinez1 and Frédéric Jaisser1,2
1 INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France; 2 INSERM, Clinical Investigation Centre
1433, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Nancy, France
Correspondence: Frederic Jaisser (frederic.jaisser@inserm.fr)
Neutrophil gelatinase-associated lipocalin (NGAL) is a small circulating protein that is highly

modulated in a wide variety of pathological situations, making it a useful biomarker of various
disease states. It is one of the best markers of acute kidney injury, as it is rapidly released
after tubular damage. However, a growing body of evidence highlights an important role
for NGAL beyond that of a biomarker of renal dysfunction. Indeed, numerous studies have
demonstrated a role for NGAL in both cardiovascular and renal diseases. In the present
review, we summarize current knowledge concerning the involvement of NGAL in cardio-
vascular and renal diseases and discuss the various mechanisms underlying its pathological
implications.
Introduction
Neutrophil gelatinase-associated lipocalin (NGAL), also known as lipocalin-2, 24p3, siderocalin, or ute-
rocalin, is a small secreted glycoprotein of 25 kDa. NGAL was initially identified in mature neutrophil
granules [1], but has since been described in many other cell types. NGAL is expressed in renal [2], en-
dothelial [3], liver [4], and smooth muscle cells (SMCs) [5], as well as cardiomyocytes [6], neurons [7],
and various populations of immune cells, such as macrophages [5,8] and dendritic cells [9].
Several roles have been ascribed to NGAL, including iron trafficking [10] and chemotactic [11,12] and
bacteriostatic [13] effects. It can also promote differentiation and proliferation, and act as a growth factor
[14]. The effects of NGAL are mediated through two different receptors, 24p3R and megalin, depending
on the tissue. NGAL is used as a renal injury biomarker because it is rapidly released in response to tubular
damage [15,16]. However, numerous studies show that NGAL is more than a simple biomarker, and that
it plays an important role in the pathophysiology of renal and cardiovascular diseases. Moreover, NGAL
is involved in various deleterious processes, such as inflammation and fibrosis.
The lipocalin family

NGAL is a member of the lipocalin protein family. This family includes many small proteins, most of
which act as transporters, mainly for lipophilic substances. However, other roles for these proteins have
been discovered, such as the regulation of cell division, differentiation, cell–cell adhesion, and cell survival
[17]. Members of most protein families are identified based on similarities in their amino acid sequences,
but members of the lipocalin family share a common 3D structure necessary for their transport function:
the lipocalin fold. This structure is composed of eight anti-parallel sheets forming a cup-shaped cavity that
Received: 21 December 2017 serves as a ligand-binding site (Figure 1) [17,18]. Differences in amino acid sequences between members of
Revised: 05 March 2018 the lipocalin family can be very large (up to 80%), allowing binding to a wide variety of ligands within the
Accepted: 04 April 2018 family [17,18]. However, three domains are very well-preserved and distinguish two branches of lipocalins:
Version of Record published: the “Kernel” branch, which has three preserved domains (such as NGAL), and the “Outliers” that only
08 May 2018 have two. (Figure 1) [17,18].

c 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society 909
https://doi.org/10.1042/CS20171592
Figure 1. Schematic structure of lipocalins

(A) Schematic representation of the lipocalin fold. The areas boxed in blue correspond to the domains structurally preserved within
the lipocalin family and the region boxed in black corresponds to a domain showing significant conservation in amino acid sequence.
Adapted from Chakraborty et al. [17]. (B) Tridimensional structure of lipocalins. Adapted from Candido et al. [134].
Structure of NGAL
Like other members of the lipocalin family, NGAL has a 3D barrel structure. Its binding site, however, has two partic-
ularities: it is polar and it is wide enough to bind to certain proteins [13]. In addition, the presence of a cysteine residue
at position 87 allows NGAL to form a disulfide bridge with a specific ligand, matrix metalloproteinase-9 (MMP-9,
also known as gelatinase B) [19], a protein of which the enzymatic action allows the degradation of certain extra-
cellular matrix (ECM) components and is therefore involved in tissue remodeling mechanisms [20]. The binding of
MMP-9 to NGAL does not modify its activity, but stabilizes the protein and decreases its degradation [19].
A comparison of the sequences of NGAL between different species revealed the greatest similarity between human
and chimpanzee (98%). However, the structure between human NGAL and mouse or rat NGAL has little similarity
(62% and 63% respectively) [17]. The cysteine 87 residue, present in human NGAL, is absent from that of rodents,
suggesting that the NGAL/MMP-9 interaction is not possible in rodents. This inability of mice NGAL to form het-
erodimers with the MMP-9 was demonstrated by Cramer et al. [21] in tumors and myeloid cells from wild-type and
NGAL knockout mice and compared with human myeloid cells. The mouse ortholog contains two cysteines which
are both unable to form homodimers and heterodimers since they are engaged in an intramolecular disulfide loop
[21]. These discrepancies could explain differences found in NGAL function between mice and human such as NGAL
role in apoptosis for example. Indeed, while mouse NGAL has been showed to be involved in apoptotic mechanisms
[22], a study by Klausen et al. [23] indicates that these effects are not found in human myeloid cells.
On the other hand, other studies showed a functional relationship between NGAL and MMP-9 in rodents. NGAL
has been detected in a complex with MMP-9 in the supernatant of a culture of rat SMCs [24] and colocalized with
MMP-9 in mouse atheroma plaques [25].
Apart from MMP-9, NGAL is also able to interact with other ligands, particularly certain bacterial siderophores
(Figure 2).
Roles of NGAL
Role of NGAL in iron binding and modulation
As mentioned above, NGAL is involved in antibacterial defense through iron sequestration. Iron is an essential ele-
ment for the development of bacteria, but is present in very small quantities in the body. Bacteria capture iron from
the host by releasing proteins with a high affinity for iron, i.e. siderophores. In vitro studies have shown that NGAL
can bind to bacterial siderophores, thus playing a bacteriostatic role by reducing iron availability [13]. In addition,
genetic invalidation of NGAL in mice (NGAL KO) increased their susceptibility to bacterial infections [26].
NGAL can also bind to endogenous siderophores present in humans, i.e. catechols, suggesting a role for NGAL in
iron homeostasis, even in the absence of bacterial infection [10]. When NGAL binds to an iron-coupled siderophore
(holo-NGAL form), it transports iron into the cell, thus increasing the cytosolic iron concentration (Figure 3A). Con-
versely, when it is free (apo-NGAL form), it allows the capture of intracellular iron and its transport to the extracellular
space, thus decreasing the intracellular iron concentration (Figure 3B) [27]. This role of NGAL in iron homeostasis
may have a significant impact on pathology as iron levels play an important role in various deleterious mechanisms,
such as oxidative stress [28], inflammation [29], apoptosis [28,30], and fibrosis [30].
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c 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
https://doi.org/10.1042/CS20171592
Figure 2. 3D structure of the NGAL–siderophore–iron complex

3D representation of NGAL in humans (A) and mice (B). The red sphere in the center corresponds to an iron atom and the surrounding
structure corresponds to a siderophore. Adapted from Xiao et al. [135]. (C) Representation of a siderophore–iron complex to which
NGAL can bind. The atoms are identified by their color: C in grey, N in blue, and O in red. The red sphere corresponds to the iron
atom in the center of the siderophore. Adapted from Goetz et al. [13].
Figure 3. Role of NGAL in iron trafficking

(A) Importation of iron into the cell. NGAL bound to an iron-coupled siderophore (holo-NGAL) is endocytosed in the cell through
its membrane receptor (Megalin or 24p3R), thus allowing the release of iron into the cytoplasm. The increase in cytoplasmic iron
levels induces the expression of iron-dependent genes and promotes oxidative stress which, in turn, activates the NF-kB pathway,
known to be involved in inflammatory and fibrotic mechanisms; ROS, reactive oxygen species. (B) Exportation of iron out of the
cell. Free NGAL (apo-NGAL) is endocytosed into the cell where it binds to an iron-coupled siderophore. It is then exocytosed from
the cell, thus allowing the release of iron into the extracellular medium and diminution of the intracellular iron stock.
Chemotactic role of NGAL

NGAL has proinflammatory and chemotactic properties. Treatment of neutrophils in culture with recombinant
NGAL induces their migration [11,12]. In addition, neutrophils from NGAL KO mice show reduced chemotaxis
and adhesion [11]. Neutrophil infiltration into the dermis was also reduced in mice treated with an anti-NGAL an-
tibody and increased by in vivo treatment with recombinant NGAL in a mouse model of psoriasis (inflammatory
skin disease) [12]. The recruitment of immune cells to the heart of mice subjected to an ischemia/reperfusion (I/R)
episode is blunted in NGAL KO mice [31]. When hearts from NGAL KO mice were transplanted into WT recipients,
granulocyte infiltration was significantly less than that observed for a WT to WT heart transplant [31]. Numerous ex-
periments carried out in cellular and murine cancer models have also demonstrated a role for NGAL in cell migration
and invasion [32-34].

https://doi.org/10.1042/CS20171592
Role of NGAL in differentiation and proliferation and as growth factor

NGAL has also been shown to promote differentiation and proliferation, acting as a growth factor [14]. NGAL stim-
ulates the proliferation and epithelial differentiation of rat embryonic kidney cells and can induce the tubular or-
ganization of mouse epithelial cells in culture [35]. NGAL also induces the proliferation of human vascular SMCs
[36] and cardiac fibroblasts [37]. The role of NGAL in cell proliferation has also been demonstrated in gastric and
thyroid cancer models [38,39]. NGAL participates in the epithelial–mesenchymal transition in vivo in a pulmonary
adenocarcinoma model in mice [40] and in vitro in prostate [32] and breast cancer cells [41]. In these models, NGAL
promoted the motility, invasiveness, and metastatic capacities of cancer cells.
NGAL receptors
24p3 receptor
The 24p3 receptor (24p3R) is one of two receptors currently described for NGAL. 24p3R is an endocytic receptor
with a strong affinity for NGAL, allowing it to enter cells. It participates in the control of iron homeostasis by allowing
NGAL to enter the cells, thus modulating intracellular iron concentrations. The expression of this receptor has been
shown in various tissues and the heart [27]. Under inflammatory conditions, 24p3R is expressed in the entire heart
and, in particular, on the surface of cardiomyocytes [42]. In addition, 24p3R is expressed in distal renal nephrons [43]
and is involved in albumin endocytosis and activation of the proinflammatory and profibrotic signaling pathways of
NF-κB and TGF-β [44]. 24p3R expression is elevated on the surface of neutrophils of psoriasis patients [12]. Finally,
an anti-24p3R siRNA has been used to highlight the important role of this receptor in the activation of neutrophils
by NGAL in culture [12].
Megalin
The other known receptor for NGAL is megalin (or low-density lipoprotein receptor-related protein 2). Megalin is
a multiligand endocytic receptor expressed by various epithelia, in particular, epithelia with high absorptive capac-
ity, such as the epithelium of the renal tubule, ileum, and choroid plexus in the brain [45]. Megalin has also been
detected in cardiomyocytes cultured in vitro [46] as well as various types of immune cells, such as T cells, B cells,
granulocytes, and monocytes/macrophages [47]. Megalin belongs to the family of low-density lipoprotein receptors
[48] and binds to various lipocalins [18,49]. However, its affinity for NGAL is higher than for other lipocalins [50].
The pathophysiological role of the NGAL–megalin complex is still not well described.
Involvement of NGAL in renal pathologies

NGAL has been described as an acute renal lesion biomarker because it is rapidly released in response to tubular
damage [15,16]. It is a secreted protein and can be quantified in plasma or serum. The plasma concentration of NGAL
is approximately 70 ng/ml [51] in healthy humans and 100 ng/ml in mice [8,52]. NGAL levels can also be measured
in urine [53]. These elements, combined with its good stability and resistance to proteases, make it a biomarker of
choice for clinical use [15,16]. Creatinine plasma levels are commonly used to evaluate renal function. However, an
ever-growing number of studies describe NGAL as a better marker of acute kidney injury (AKI).
NGAL in AKI
It is considered that traditional markers of kidney injury, such as creatinine and blood urea nitrogen, are neither sen-
sitive nor specific for the diagnosis of AKI. Changes in these traditional markers are significant only after important
kidney injury and a substantial time delay. They are therefore not optimal to achieve early diagnosis of AKI [54,55].
Efforts to identify biomarkers to assist with this diagnosis have revealed several promising candidates such as kidney
injury molecule-1, interleukin-18, cystatin C, clusterin, fatty acid-binding proteins, osteopontin, and NGAL [55].
In animals, ischemia/reperfusion (I/R) induces a massive increase in renal NGAL levels within 3 h after ischemia,
whereas the increase in serum creatinine levels is still only moderate at this time point [56]. In addition, serum crea-
tinine concentrations increase after severe bilateral ischemia, but remain unchanged after mild bilateral or unilateral
ischemia [56]. In AKI, NGAL levels increase up to 300-fold in blood (0.1–30 μg/ml) and 1000-fold in urine (0.04–40
mg/ml) [52,56].
The relative level of serum NGAL in patients with AKI correlates with the severity of renal damage and high
levels of serum NGAL are associated with an increased risk of mortality [57]. In addition, urinary and serum NGAL
concentrations have been shown to be sensitive, specific, and highly predictive markers of AKI after cardiac surgery
[53].
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In a study performed by Woodson et al. [58], the authors analyzed cystatin C and NGAL urinary levels at different
times in an animal model of kidney injury. Both biomarkers increased after renal clamping. Both appear to be useful
biomarkers of renal injury. Both markers showed a peak level of damage at 30 min. However, an important point to
highlight is that cystatin C levels decrease with time after injury while NGAL levels continue to increase or remain
elevated, making it useful for a long time to allow diagnosis [58]. Another study demonstrated that NGAL and cystatin
C in combination have been shown to be independent predictors of the duration and severity of AKI after adult cardiac
surgery patients, showing that combination of different biomarkers could be the best option to measure kidney injury
[59].
Several studies have also suggested NGAL as a marker of renal damage in pathological contexts broader than renal
ischemia, such as glomerulonephritis and IgA nephropathy [60,61].
Paragas et al. [62] have studied the origin of NGAL during AKI using a mouse model expressing a bioluminescent
reporter of NGAL expression. They determined that NGAL was synthesized by cells of the thick ascending limb of
Henle’s loop and the collecting duct, only in ischemic areas of the kidney, during I/R. In addition, they demonstrated
that the increase in urinary NGAL concentrations during renal ischemia is mainly due to the release of NGAL origi-
nating in the kidney, by performing kidney transplants between WT and NGAL KO mice, and that the contribution
of extrarenal NGAL to urinary NGAL is small [62].
Another suggested source of urinary NGAL, especially in nonrenal diseases, has been circulating NGAL of extra
renal origin released into systemic circulation at sites of inflammation, notably by immune cells [63], and then filtered
by the renal glomerulus. Most NGAL would then be reabsorbed by the proximal tubule, which expresses megalin, and
the remaining NGAL would be excreted in the urine. This has been illustrated by a study showing that mice deficient
for megalin show leakage of NGAL into the urine [50].
Beyond its role as a biomarker, NGAL is actively involved in the mechanisms underlying kidney damage. It has
been shown to play a protective role in AKI after an episode of I/R [52,64]. During an I/R episode, the release of large
amounts of iron at the time of ischemia promotes oxidative stress and induces tissue damage. In addition, subsequent
reperfusion further increases the amount of iron, exacerbating the damage caused by oxidative stress [65,66]. The
use of iron-binding proteins [67,68] in animal models, including the injection of recombinant NGAL [52,64], has
been shown to limit early damage caused by I/R or graft rejection following renal transplantation [69]. A study also
showed that intravenous injection of macrophages overexpressing the anti-inflammatory cytokine IL-10 could protect
against renal ischemia in rats and improve cell regeneration and tissue repair through the induction of NGAL [70].
The protective role of the adoptive transfer of macrophages overexpressing IL-10 was lost when the rats were treated
with an anti-NGAL antibody [70], underlying the crucial role of NGAL. More recently, a study showed that infusion
of macrophages overexpressing NGAL could improve renal fibrosis in a unilateral ureteral obstruction model in mice
[71].
NGAL in chronic kidney disease (CKD)

In contrast with its protective effect in AKI, NGAL is harmful in the long term. It is considered to be a proinflam-
matory factor that promotes progression to CKD [72,73]. NGAL levels are elevated in CKD patients [73,74] and
mouse models of CKD [72,73] and correlate with the severity of renal injury. Indeed, a high level of urinary NGAL
is associated with a higher risk of CKD [73,75].
The role of NGAL in CKD has been investigated in animal models, particularly using NGAL KO mice. NGAL
gene invalidation protected mice from proteinuria and tubular lesions in glomerulonephritis model induced with
an anti-glomerular basement membrane antibody, whereas the addition of recombinant NGAL exacerbated kidney
disease and decreased survival [72]. Similarly, NGAL KO mice exhibited less apoptosis, fewer renal lesions (glomeru-
losclerosis, tubular atrophy, interstitial fibrosis, and immune infiltration), less proteinuria, and better renal function
than WT mice in a subtotal nephrectomy-induced CKD model [73]. However, the inhibition of apoptosis observed in
NGAL KO mice was not observed in tubular cells with NGAL silencing [73]. This study also showed that NGAL is an
effector of the proliferative effects of the epidermal growth factor receptor [73], which is known to play an important
role in the progression of CKD [76].
In conclusion, the role of NGAL in kidney disease appears to depend on the associated pathological mechanisms:
after AKI, NGAL plays a protective role, notably via its iron-modulating effects, whereas its proinflammatory and
proliferative effects make it a harmful actor in more chronic contexts.

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Involvement of NGAL in cardiovascular diseases

Aside from its role as a biomarker of kidney lesions and its involvement in the pathophysiology of renal diseases,
NGAL has also been shown to be associated with the development of cardiovascular (CV) diseases such as myocardial
infarction, heart failure, atherosclerosis, cardiovascular ischemia, aortic aneurysm, and cardiometabolic disorders as
described below.
NGAL in myocardial infarction and heart failure

Several studies have documented elevated circulating NGAL levels in patients with CV disease [77,78]. Serum NGAL
levels are higher in patients with acute myocardial infarction (MI) or chronic heart failure (HF) than in healthy
subjects [77,79] and are also higher in MI patients than those with stable coronary heart disease [80]. Several studies
suggest that NGAL may have prognostic value in HF patients, because high levels of plasma or urinary NGAL are
associated with more renal complications [77,79,81] or mortality [82-84]. A higher basal level of NGAL was associated
with an increase in the proportion of adverse cardiac events and overall all-cause mortality in a 10-year follow-up
study of healthy subjects [85]. Such high NGAL levels may be explained, in part, by the renal failure observed in a
large number of HF patients [86]. However, several studies have shown that NGAL was a predictor of CV incidents,
even in the absence of renal dysfunction [87-89]. Circulating NGAL levels have also been reported to be predictors
of CV complications in patients with CKD [90,91].
In animals, NGAL production increases in the heart and aorta after MI [25,79]. NGAL production also increases in
isolated rat cardiomyocytes in response to stimulation by various proinflammatory molecules, such as endothelin-1,
IL-1, and TNF-α [79]. In a recent study from our laboratory, we demonstrated that NGAL KO mice showed decreased
cardiac fibrosis and inflammation, as well as preserved cardiac function, 3 months after MI [92,93]. A recent study
from Sung et al. [94], using a similar MI model, showed that NGAL KO mice exhibit increased autophagy, associated
with decreased apoptosis and preserved cardiac function, after infarction.
NGAL in atherosclerosis
NGAL expression has been observed in endothelial cells, SMCs, and macrophages and is higher in the arteries of
atherosclerotic patients with symptomatic carotid stenosis than those of asymptomatic patients [5]. The level of cir-
culating NGAL is also associated with plaque vulnerability [95]. Serum NGAL levels on admission are associated with
increased burden of atherosclerosis in patients with non-ST elevation acute coronary syndrome [96]. It has been sug-
gested that NGAL is involved in systemic inflammation and endothelial dysfunction leading to atherosclerosis plaque
formation [97]. In addition, NGAL expression colocalized with macrophages and that of MMP-9 in atherosclerotic
plaques in a mouse atherosclerosis model, suggesting a possible role of NGAL in MMP-9-mediated remodeling [25].
MMP-9 leads to modification of the coronary plaque promoting myocardial infarction due to the rupture of the cap.
NGAL binds to MMP-9 resulting in sustained MMP-9 activity allowing increased vulnerability of the plaque [97].
NGAL in cardiovascular ischemia

A role for NGAL has also been shown in the development of cardiac lesions following I/R [98,99]. NGAL KO hearts
exhibited a smaller infarct size and better cardiac contractile function than WT hearts after an episode of I/R in a
model of isolated-perfused heart [99]. In addition, increasing NGAL circulating levels of NGAL KO mice using an
NGAL encoding adenovirus resulted in impaired recovery of cardiac function and decreased mitochondrial func-
tion of the isolated-perfused hearts [99]. In contrast, the use of anti-NGAL antibodies reduced the infiltration of
macrophages and neutrophils into the ischemic zone, suppressed the M1 polarization of macrophages, and blunted
the I/R-induced cardiac lesions in a mouse model of I/R after heart transplantation [98].
A large increase in NGAL and MMP-9 levels has been observed in the intima of the common carotid artery in a
rat model of cerebrovascular ischemia [24]. In this model, blocking the NF-κB pathway in vivo led to almost total
suppression of NGAL and MMP-9 expression, suggesting a central role for NF-κB signaling in the regulation of NGAL
and MMP-9 transcription in this context [24]. In vitro IL-1β treatment also induced expression of NGAL in cultured
SMCs in an NF-κB-dependent manner [24].
NGAL in abdominal aortic aneurysm

The analysis of biopsies from patients with abdominal aortic aneurysm (AAA) has shown the expression of the
NGAL/MMP-9 complex in the vascular wall and thrombus present in the blood vessel lumen [100]. Neutrophils
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were the major source of NGAL expression in this context. The absence of NGAL (in NGAL KO mice) or its block-
ade (with anti-NGAL antibodies) had the same protective effects against the development of AAA in a mouse AAA
model, with decreased neutrophil infiltration and MMP activity [101].
NGAL in cardiometabolic disorders

Circulating NGAL levels are elevated in obesity in humans and animals and correlate with elevated blood pressure and
insulin resistance [102]. A recent study from our laboratory also reported elevated plasma levels of the NGAL/MMP-9
complex in a cohort of obese patients that correlated with elevated levels of circulating fibrosis markers [103].
In animal models of obesity, NGAL KO mice were protected against hypertension [104] and inflammation
[104,105], as well as endothelial [106] and cardiometabolic dysfunction [99,105,106] induced by a high fat diet. Song
et al. [104] reported that the deamidation of NGAL (by linoleic acid, in particular) improved its stability and pro-
moted its accumulation. The combined administration of recombinant NGAL and linoleic acid in WT mice promoted
oxidative stress, endothelial dysfunction, inflammation, and hypertension [104].
NGAL and iron metabolism in cardiomyopathies

Both iron overload and iron deficiency have been linked to cardiomyopathies: iron overload has been associated
with increased oxidative stress and iron deficiency, resulting in mitochondrial dysfunction, impaired cardiac function
[107], hypercoagulation, and anemia-associated oxidative stress [108]. The involvement of NGAL in iron homeostasis
may thus play an important role in the development of some cardiomyopathies. Indeed, NGAL has also been shown
to participate in cardiomyocyte apoptosis resulting from intracellular iron accumulation [22]. The apoptosis of car-
diomyocytes may thus influence the remodeling process involved in the development of certain cardiac pathologies,
underlying the potential involvement of NGAL in this process.
Involvement of NGAL in inflammatory mechanisms

NGAL and proinflammatory cytokine expression
Serum or plasma levels of NGAL have been shown to correlate with those of other inflammatory markers, such as
TNF-α, CRP, IL-6, and leukocyte number, in heart failure and various other inflammatory pathologies [109,110].
NGAL expression can be induced by various proinflammatory stimuli, such as LPS [111], IL-1β [112], IL-6 [3],
IL-17 [113], IFN-γ [114], and TNF-α [79], depending on cell type. Furthermore, NGAL expression is positively reg-
ulated by the activation of the NF-κB pathway [24], which is known for its role in proinflammatory mechanisms.
Conversely, NGAL can itself activate the NF-κB pathway [115,116], and induce the expression of diverse proinflam-
matory molecules, such as IL-8 [5,12], IL-6 [5,12], IL1-α [12], TNF-α [12], and MCP-1 [5]. Finally, it has been shown
that NGAL is involved in the polarization of macrophages toward the proinflammatory phenotype M1, in vitro and
in vivo [98,117].
Altogether, these data suggest the existence of a vicious circle in which NGAL is overexpressed in inflammatory
conditions and can, in turn, further potentiate inflammation by inducing the expression of proinflammatory media-
tors (Figure 4).
NGAL and inflammatory diseases

NGAL has been proposed to be involved in chronic inflammation and autoimmune diseases. Urinary levels of NGAL
are elevated in patients with lupus nephropathy and are associated with the severity of the disease [118]. NGAL is
strongly expressed in cardiomyocytes, vascular SMCs, fibroblasts, and neutrophils in a rat autoimmune myocarditis
model [42] and was particularly high during the active phase of myocarditis and closely followed cardiac and plasma
IL-1β levels [42]. NGAL KO mice showed 50% less inflammation associated with reduced immune infiltration than
WT mice in an acute antibody-induced skin inflammation model [119]. The same benefit was found by injecting WT
mice with anti-NGAL antibodies, whereas inflammation was restored by treatment with recombinant NGAL [119].
NGAL expression by immune cells

NGAL expression was first described in neutrophils [1] and later observed in other immune cell types such as
macrophages [5,8] and dendritic cells [9]. Recent studies suggest that the expression of NGAL by these immune
cell types may be important in the regulation of inflammatory processes. It has been shown, for example, that NGAL
secreted by dendritic cells is involved in the activation and polarization of T-cells toward a proinflammatory phe-
notype [9]. Gilet et al. [120] showed that aldosterone could induce the production of NGAL by human neutrophils

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Figure 4. Involvement of NGAL in a proinflammatory amplification loop

NGAL expression is induced by several proinflammatory cytokines, as well as NF-κB pathway activation. NGAL itself has proinflam-
matory effects, inducing the expression of various proinflammatory cytokines and activation of the NF-κB pathway. NGAL is also
involved in the polarization of macrophages toward the proinflammatory phenotype, M1; M, macrophage; M1, proinflammatory
M1 macrophage.
complexed with MMP-9. Aigner et al. [31] identified neutrophils as the primary source of NGAL released at the time
of immune infiltration in the mouse heart after an episode of I/R.
A recent study from our laboratory, using mice in which NGAL was depleted from their immune cells only (after
bone marrow transplantation), allowed us to demonstrate the pivotal role of NGAL produced by immune cells in
promoting the deleterious effects on the heart and kidneys following mineralocorticoid challenge [37]. This challenge
induced systemic inflammation and induction of NGAL expression by macrophages, dendritic cells, and peripheral
blood mononuclear cells in WT mice. The depletion of NGAL from immune cells protected the mice against cardiac
and renal remodeling, as well as inflammation induced by mineralocorticoid excess [37]. Of note, mice with NGAL
depleted from their immune cells presented lower levels of cardiac NGAL than control mice, revealing immune cells
to be a major source of NGAL in the heart [37].
Involvement of NGAL in hypertensive mechanisms

Plasma NGAL levels are higher in patients with essential hypertension than healthy subjects and correlate with blood
pressure [121]. Polymorphisms in the NGAL promoter have been associated with changes in blood pressure in clinical
studies [122].
The role of NGAL in hypertensive mechanisms has also been demonstrated in animal models of obesity. NGAL
KO mice are protected against hypertension, inflammation, and cardiometabolic dysfunction induced by a high fat
diet [104-106]. The direct role of NGAL in blood pressure control has been further demonstrated by the combined
administration of recombinant NGAL and linoleic acid in mice, which induced an increase in blood pressure [104].
Recently, a study from our laboratory demonstrated the crucial role of NGAL in regulating aldosterone-mediated
hypertension. Indeed, global genetic inactivation of NGAL in mice prevents the increase in blood pressure induced
by a mineralocorticoid challenge [103].
Involvement of NGAL in profibrotic mechanisms

The role of NGAL in profibrotic mechanisms was first suggested by the identification of its binding to MMP-9, a
protein involved in ECM remodeling [19]. Our laboratory recently demonstrated the crucial role of NGAL in the
profibrotic effects following mineralocorticoid challenge [103] and in a model of MI [92].
The mechanisms by which NGAL induces fibrosis are probably diverse. NGAL binding to MMP-9 may be one,
although whether NGAL/MMP-9 complexes occur in rodents is still a matter of debate. It is also possible that NGAL
binds to other molecules that modulate fibrosis. For example, NGAL binds and negatively regulates the activity of
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hepatocyte growth factor, a peptide known for its antifibrotic properties [123]. We recently showed a direct profi-
brotic role of NGAL in human cardiac fibroblasts [37,92]. The treatment of fibroblasts with aldosterone induced
the expression of NGAL and collagen I. However, inhibition of NGAL expression by siRNA resulted in the loss of
aldosterone-induced collagen I expression, suggesting that NGAL may act as a mediator of the profibrotic effects of
aldosterone in vivo [92].
In addition, our data show that NGAL influences the proliferation of fibroblasts in vitro [37]. This proliferative
effect of NGAL has also been described in vivo in renal I/R models, in which recombinant NGAL injection induced
tubular cell proliferation [52,64], whereas NGAL KO mice showed reduced tubular proliferation in a mouse model
of CKD [73]. Given the key role of proliferation (particularly myofibroblasts) in the mechanisms of remodeling and
fibrosis [124], the proliferative effects of NGAL may also be involved in pathological organ remodeling.
Signaling pathways involved in the pathological effects of

NGAL
Erk1/2 signaling pathway
Another signaling pathway regulated by NGAL is the ERK1/2 pathway. This signaling pathway is known for its in-
volvement in cell proliferation and cell death processes [125]. Aldosterone has been shown to induce the formation
of NGAL/MMP-9 complexes in human neutrophils in culture, and this effect was prevented by an ERK1/2 inhibitor
[120]. The role of the ERK1/2 pathway in the induction of NGAL synthesis has also been described in intestinal epithe-
lial cells in response to a bacterial toxin [126]. Expression of the NGAL receptor, 24p3R, was also induced in human
mesangial cells in culture by IL-1β and also involved activation of the ERK1/2 signaling pathway [127]. Conversely,
several studies have shown that NGAL can activate the ERK1/2 signaling pathway and that this pathway is involved
in the cellular effects of NGAL. Treatment of cultured epithelial cells with NGAL induces activation of the ERK1/2
pathway and cell migration, which was lost following inhibition of this signaling pathway [35]. Similarly, treatment
of human neutrophils in culture with recombinant NGAL stimulates cell migration and proinflammatory cytokine
expression via the 24p3R receptor and induction of the ERK1/2 signaling pathway [12]. Overexpression of NGAL or
treatment with recombinant NGAL activated the ERK1/2 pathway in models of esophageal [33] and prostate cancer
cells [128]. Inhibition of this pathway also blocked the migration and invasive properties of the cells promoted by
NGAL.
NF-κB signaling pathway

A large number of studies have shown that the NF-κB pathway controls the expression of NGAL [4,24,38,39]. Con-
versely, some have shown that NGAL itself can activate the NF-κB pathway [40,115,116], which is of primary im-
portance, given the major involvement of this pathway in inflammatory and fibrotic mechanisms [129,130]. Wang et
al. [116] showed, for example, that NGAL activates the NF-κB pathway via increased levels of intracellular iron and
reactive oxygen species in a cell model of NGAL overexpression. We recently showed that NGAL activates the NF-κB
pathway in cardiac cells, in vivo and in vitro, consistent with these findings [92]. The treatment of cardiac fibroblasts
with recombinant NGAL induced NF-κB activation, whereas blocking the NF-κB pathway prevented NGAL-induced
collagen I production [92]. The NF-κB pathway was activated in WT mice 7 days after MI, but it was not activated
in NGAL KO mice, demonstrating the importance of NGAL in activating this pathway in vivo [92]. These findings
highlight the importance of the NF-κB pathway in mediating the direct profibrotic effects of NGAL.
Conclusion
In conclusion, NGAL appears to be an important mediator of cardiac and renal diseases through its role in hyperten-
sion, inflammation, and fibrosis. High levels of NGAL have been reported in a wide variety of pathological situations,
both in animals and patients, and NGAL blockade by neutralizing antibodies or genetic inactivation is beneficial in
animal models of cardiac and renal injuries. The role of NGAL in inflammation is particularly important, as it is
part of a proinflammatory amplification loop. NGAL is induced in inflammatory situations and can itself amplify in-
flammation by stimulating the production of proinflammatory cytokines and activating proinflammatory pathways,
as well as polarizing immune cells toward proinflammatory phenotypes. This proinflammatory role of NGAL may
be important in its effects on hypertension and fibrosis, as the interconnection of these pathological mechanisms is
now well described [131-135]. Finally, NGAL production and secretion by immune cells themselves seem to play an
important role in certain cardiorenal pathological situations. The role of NGAL produced by specific immune cell
populations should thus be further studied.

https://doi.org/10.1042/CS20171592
Given the role of NGAL in pathological processes, it may represent a promising therapeutic target in CV and renal
diseases, and beyond, especially those involving inflammatory mechanisms.
Competing Interests
The authors declare that there are no competing interests associated with the manuscript.
Funding
This work was funded by grants from the Institut National de la Santé et de la Recherche Médicale, Fondation de France
[2014-00047968]; ANR MRFOCUS [ANR-15-CE14-0032-02]; and the Fight-HF Avenir investment program [ANR-15-RHUS-0004].
M.B. was supported by a PhD grant from Region Ile de France CORDDIM.
Author Contribution
Drafting original manuscript: M.B.; Reviewing and editing: M.B., E.M.-M., and F.J.; Validation: M.B., E.M.-M., and F.J.; Supervision
and funding acquisition: F.J.
Abbreviations
AAA, abdominal aortic aneurysm; AKI, acute kidney injury; CKD, chronic kidney disease; CRP, C reactive protein; CV,
cardiovascular; ECM, extracellular matrix; ERK1/2, extracellular signal regulated kinase 1/2; HF, heart failure; IFN-γ,
interferon-gamma; IL, interleukin; I/R, ischemia/reperfusion; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant
protein-1; MI, myocardial infarction; MMP-9, matrix metalloproteinase-9; NF-κB, nuclear factor-kappa B; NGAL, neutrophil
gelatinase-associated lipocalin; SMC, smooth muscle cell; TGF-β, transforming growth factor-beta; WT, wild type.
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NGAL role in cardio-renal diseases

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Clinical Science (2018) 132 909–923

More than a simple biomarker: the role of NGAL in

Neutrophil gelatinase-associated lipocalin (NGAL) is a small circulating protein that is highly

The lipocalin family

Figure 1. Schematic structure of lipocalins

Figure 2. 3D structure of the NGAL–siderophore–iron complex

Figure 3. Role of NGAL in iron trafﬁcking

Chemotactic role of NGAL

Role of NGAL in differentiation and proliferation and as growth factor

Involvement of NGAL in renal pathologies

NGAL in chronic kidney disease (CKD)

Involvement of NGAL in cardiovascular diseases

NGAL in myocardial infarction and heart failure

NGAL in cardiovascular ischemia

NGAL in abdominal aortic aneurysm

NGAL in cardiometabolic disorders

NGAL and iron metabolism in cardiomyopathies

Involvement of NGAL in inﬂammatory mechanisms

NGAL and inﬂammatory diseases

NGAL expression by immune cells

Figure 4. Involvement of NGAL in a proinﬂammatory ampliﬁcation loop

Involvement of NGAL in hypertensive mechanisms

Involvement of NGAL in proﬁbrotic mechanisms

Signaling pathways involved in the pathological effects of

NF-κB signaling pathway

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