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Aquaporins in sepsis- an update
Katharina Rump*and Michael Adamzik
Klinik für Anästhesiologie Intensivmedizin und Schmerztherapie Universitätsklinikum
Knappschaftskrankenhaus Bochum, University Clinic of Ruhr University Bochum, Bochum, Germany
Aquaporins (AQPs), a family of membrane proteins that facilitate the transport of
water and small solutes, have garnered increasing attention for their role in
sepsis, not only in fluid balance but also in immune modulation and metabolic
regulation. Sepsis, characterized by an excessive and dysregulated immune
response to infection, leads to widespread organ dysfunction and significant
mortality. This review focuses on the emerging roles of aquaporins in immune
metabolism and their potential as therapeutic targets in sepsis, with particular
attention to the modulation of inflammatory responses and organ protection.
Additionally, it explores the diverse roles of aquaporins across various organ
systems, highlighting their contributions to renal function, pulmonary gas
exchange, cardiac protection, and gastrointestinal barrier integrity in the
context of sepsis. Recent studies suggest that AQPs, particularly
aquaglyceroporins like AQP3, AQP7, AQP9, and AQP10, play pivotal roles in
immune cell metabolism and offer new therapeutic avenues for sepsis treatment.
In the context of sepsis, immune cells undergo metabolic shifts to meet the
heightened energy demands of the inflammatory response. A key adaptation is
the shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, where
pyruvate is converted to lactate, enabling faster ATP production. AQPs,
particularly aquaglyceroporins, may facilitate this process by transporting
glycerol, a substrate that fuels glycolysis. AQP3, for example, enhances glucose
metabolism by transporting glycerol and complementing glucose uptake via
GLUT1, while also regulating O-GlcNAcylation, a post-translational modification
that boosts glycolytic flux. AQP7 could further contributes to immune cell energy
production by influencing lipid metabolism and promoting glycolysis through
p38 signaling. These mechanisms could be crucial for maintaining the energy
supply needed for an effective immune response during sepsis. Beyond
metabolism, AQPs also regulate key immune functions. AQP9, highly
expressed in septic patients, is essential for neutrophil migration and activation,
both of which are critical for controlling infection. AQP3, on the other hand,
modulates inflammation through the Toll-like receptor 4 (TLR4) pathway, while
AQP1 plays a role in immune responses by activating the PI3K pathway,
promoting macrophage polarization, and protecting against lipopolysaccharide
(LPS)-induced acute kidney injury (AKI). These insights into the
immunoregulatory roles of AQPs suggest their potential as therapeutic targets
to modulate inflammation in sepsis. Therapeutically, AQPs present promising
targets for reducing organ damage and improving survival in sepsis. For instance,
inhibition of AQP9 with compounds like HTS13286 or RG100204 has been
shown to reduce inflammation and improve survival by modulating NF-kB
signaling and decreasing oxidative stress in animal models. AQP5 inhibition
with methazolamide and furosemide has demonstrated efficacy in reducing
immune cell migration and lung injury, suggesting its potential in treating acute
lung injury (ALI) in sepsis. Additionally, the regulation of AQP1 through non-
coding RNAs (lncRNAs and miRNAs) may offer new strategies to mitigate organ
Frontiers in Immunology frontiersin.org01
OPEN ACCESS
EDITED BY
Pengpeng Zhang,
Nanjing Medical University, China
REVIEWED BY
Yanwen Chen,
University of Pittsburgh, United States
Mahbuba Rahman,
North South University, Bangladesh
*CORRESPONDENCE
Katharina Rump
Katharina.k.rump@rub.de
RECEIVED 12 September 2024
ACCEPTED 14 October 2024
PUBLISHED 31 October 2024
CITATION
Rump K and Adamzik M (2024) Aquaporins in
sepsis- an update.
Front. Immunol. 15:1495206.
doi: 10.3389/fimmu.2024.1495206
COPYRIGHT
© 2024 Rump and Adamzik. This is an open-
access article distributed under the terms o f
the Creative Commons Attribution License
(CC BY). The use, distribution or reproduction
in other forums is permitted, provided the
original author(s) and the copyright owner(s)
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in this journal is cited, in accordance with
accepted academic practice. No use,
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which does not comply with these terms.
TYPE Review
PUBLISHED 31 October 2024
DOI 10.3389/fimmu.2024.1495206
damage and inflammatory responses. Moreover, AQPs have emerged as
potential biomarkers for sepsis progression and outcomes. Altered expression
of AQPs, such as AQP1, AQP3, and AQP5, correlates with sepsis severity, and
polymorphisms in AQP5 have been linked to better survival rates and improved
outcomes in sepsis-related acute respiratory distress syndrome (ARDS). This
suggests that AQP expression could be used to stratify patients and tailor
treatments based on individual AQP profiles. In conclusion, AQPs play a
multifaceted role in the pathophysiology of sepsis, extending beyond fluid
balance to crucial involvement in immune metabolism and inflammation.
Targeting AQPs offers novel therapeutic strategies to mitigate sepsis-induced
organ damage and improve patient survival. Continued research into the
metabolic and immune functions of AQPs will be essential for developing
targeted therapies that can be translated into clinical practice.
KEYWORDS
aquaporin (AQP), AQP9 aquaporin-9, drug target, sepsis, pathophysiology sepsis, AQP5
aquaporin 5, AQP3, immune metabolism
1 Background
Sepsis represents a prevalent complication in Intensive Care
Units across Germany and the United States (1), with persistently
high mortality due to its complex immunological nature. In the
United States septic conditions accounts for more than $22 billion
(11.2%) of total US hospital costs in 2017 (2). Incidence and
mortality of sepsis differ among the regions worldwide. Incidence
reaches from 158/100 000 population in 2015 in Germany (3)to
780/100000 population in Sweden (4) For patients with clearly
documented sepsis (including severe sepsis), the mortality rates
from 2010 to 2015 fell from 26.6% to 23.5%, while for those with
severe sepsis alone, the rates decreased from 47.8% to 41.7%. in
Germany (5). These figures are comparable to the rates in England
(6) but significantly higher than those in the USA (15%) and
Australia (18.4%) (7,8).The absence of predictive biomarkers
specific to this syndrome prevents tailored individual therapies
based on patients’immune status. Aquaporins (AQPs) are
potential biomarkers due to their significant roles in
inflammation, particularly in sepsis, as evidenced by experimental
and association studies (9–11). AQPs are emerging as promising
candidates in sepsis research due to their significant roles in
inflammation and immune responses (12). Experimental and
association studies indicate that AQPs are not merely transport
proteins; their dysregulation is observed in immune and epithelial
cells when exposed to infectious and inflammatory stimuli (13).
Recent findings have firmly established the involvement of AQPs in
inflammatory processes, particularly since several AQP isoforms are
expressed in both innate and adaptive immune cells (14). They play
crucial roles in phagocytic functions and specific immune processes
such as cell activation and migration (15,16).
The recognition of AQPs in inflammation enhances our
understanding of the complex mechanisms governing host-
pathogen interactions. As such, AQPs represent potential
therapeutic targets for modulating edema, cell migration, and the
release of inflammatory cytokines and mediators (17,18).
Aquaporins are a family of membrane proteins that facilitate
the transport of water across biological membranes. They are
integral to maintaining water balance in cells and tissues. As
described, Aquaporins are essential for water homeostasis in all
organisms (19). These proteins are known for their remarkable
ability to transport water selectively and efficiently (20). Aquaporins
play critical roles in various physiological processes, including
kidney water conservation, brain water balance, and secretion of
cerebrospinal fluid (19).
AQPs comprise a group of 13 membrane proteins crucial for
regulating cellular water, salt fluxes, and the transport of small
solutes like glycerol, urea, and carbon dioxide (17). Water-selective
AQPs play roles in transepithelial fluid transport, cell migration,
brain edema, and neuroexcitation (17), while aquaglyceroporins are
involved in cell proliferation, adipocyte metabolism, and epidermal
water retention. Table 1 illustratesthevariousfamiliesof
aquaporins. The objective of this study is to provide an update on
the potential contributions of aquaporins (AQPs) to the
pathomechanisms of sepsis, based on the current literature
findings (21).
In conclusion, aquaporins exert a significant influence on the
pathophysiology of sepsis, affecting fluid balance, organ function
and the inflammatory response. Further research is required to fully
explore the potential of targeting aquaporins as a therapeutic
strategy. The following paragraph will delineate the role of
aquaporins in various organ systems.
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2 The significance of aquaporins in
various organ systems during sepsis
2.1 Aquaporins in whole blood of
septic patients
Aquaporins (AQPs) play a crucial role in the immune response,
with various isoforms implicated in different immune cell types and
inflammatory conditions. The AQP expression analysis in whole
blood samples from septic patients might reveal valuable AQP
biomarkers in sepsis. Our research analyzed those samples of septic
patients and revealed that AQP9 is the most abundantly expressed
aquaporin in blood, followed by AQP3, AQP5, and AQP1 (Figure 1).
In contrast AQP10, AQP7 and AQP8 very only expressed in a small
amount in whole blood (Figure 1)(23). The different expression in
whole blood could be related to different amount of blood cells, as e.g.
AQP9 is mostly expressed in high abundant neutrophils (24)and
AQP3 in the second most present T-cells (25,26). Furthermore, the
expression of these aquaporins was observed to undergo varying
changes between day 1 and day 8 of sepsis (23).
The expression of aquaporins is subject to differential regulation
in immune cells (as illustrated in Table 2 and Figure 2), and this is
further influenced by the presence of inflammatory stimuli (10,27).
It has been demonstrated that activated B and T lymphocytes
express AQP1, AQP3, and AQP5, whereas immature dendritic cells
(DCs) predominantly express AQP3 and AQP5. This expression
correlates with the activation and proliferation of these cells (13). In
leukocytes, the expression of AQP1 and AQP9 is increased
following activation or stimulation with lipopolysaccharide (LPS),
a component of bacterial cell walls. Furthermore, in cases of ICU-
acquired sepsis and SIRS, there is a notable alteration in the
expression of AQP1 and AQP9 in leukocytes, which may play a
role in cellular responses and plasma membrane dynamics under
inflammatory conditions (30–32). Furthermore, studies have
demonstrated that LPS administration results in increased AQP1
expression and decreased AQP5 mRNA levels in THP-1 cells,
underscoring the existence of isoform-specific responses in the
context of inflammation (27). It is noteworthy that elevated
AQP5 mRNA expression has been linked to unfavorable
outcomes in sepsis patients, underscoring its potential as a
prognostic marker (33).
Similarly, stimulation with lipopolysaccharide (LPS) has been
observed to upregulate AQP3 in monocytic THP-1 cells, which are
a model for studying macrophage activation and inflammation.
Inhibition or silencing of AQP3 in these cells has been
demonstrated to attenuate LPS-induced priming and reduce the
production of inflammatory cytokines such as IL-6, pro-IL-1b, and
TNF-a, indicating its involvement in Toll-like receptor 4 (TLR4)
signalling (34).
In primary human macrophages and neutrophils, AQP9 is highly
expressed and increases at both the transcript and protein levels
following LPS stimulation, indicating its role in innate immune
response modulation (34). AQP9, in particular, demonstrates
augmented expression in activated polymorphonuclear leukocytes
during systemic inflammatory response syndrome (SIRS) and
infective endocarditis (32,35). In dendritic cells (DCs), AQP9 is
TABLE 1 the different AQP subfamilies and their permeability according
to (22).
Subfamily Aquaporin permeability
Classical AQPs
(water-channels)
AQP0 H
2
O, H
2
O
2
AQP1 H
2
O, CO
2
,NH
3
AQP2 H
2
O
AQP4 H
2
O
AQP5 H
2
O, CO
2
AQP6 H
2
O (pH dependent), urea,
glycerol, nitrate
Aquaglyceroporins AQP3 H
2
O, glycerol, urea, H
2
O
2
AQP7 H
2
O, glycerol, urea, ammonia,
arsenite, NH
3
AQP9 Glycerol, NH
3
, urea, lactate,
purine, pyrimdine, H
2
O
2
AQP10 Glycerol, urea, H
2
O
Superaquaporins AQP11 H
2
O, H
2
O
2
, glycerol
AQP12 Function less well understood,
likely H
2
O
aquaammoniaporin AQP8 H
2
O, ammonia, glycerol, H
2
O
2
classical AQPs (green), Aquaglyceroporins (blue), superquaporins (orange) and
aquaammoniaporins (red) are displayed. FIGURE 1
amount of AQP expression in whole blood from high (AQP9) to low
amount (AQP8).
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markedly expressed and markedly upregulated by LPS (Figure 2).
However, the blockade of AQP9 in mice with induced colitis only
partially reduces DC inflammatory responses (36). AQP9 plays a
regulatory role in neutrophil migration and is associated with sepsis
survival. AQP9 regulates neutrophil migration and affects sepsis
survival In leukocytes, AQP9 is located at the cell edge and is
thought to be involved in motility, lamellipodium extension and
stabilisation, and changes in cell volume that facilitate migration
towards chemoattractants (37). A further study demonstrated that
the AQP9-G-quadruplex forming sequence containing long non-
coding RNA (lncRNA) axis plays a pivotal role in the exacerbation of
sepsis by promoting neutrophil activation and neutrophil
extracellular trap (NET) release (38). It can therefore be concluded
that aquaporins have specific functions in immune cells (Figure 2).
2.2 Aquaporins in sepsis-
associated encephalopathy
Aquaporins (AQPs) play an important role in several aspects of
sepsis-associated encephalopathy (SAE), a devastating complication
of sepsis characterised by vasogenic cerebral oedema and cognitive
impairment. In the context of SAE, AQPs, in particular AQP4, have
been implicated in several pathological mechanisms.
During septic encephalopathy, AQP4 is upregulated in response
to cerebral inflammation mediated by neutrophil infiltration,
exacerbating cerebral oedema (39–41)(Figure 3A). SAE is also
associated with astrocytic inflammation involving AQP4. AQP4 is
upregulated in the peripheral blood of SAE patients and in the brain
tissue of a mouse model in which AQP4 deletion can reduce
cognitive impairment by activating astrocytic autophagy and
inhibiting neuroinflammation. In addition, AQP4 knockout seem
to reduce Ca
2+
accumulation and downregulated voltage-gated,
FIGURE 2
The following schematic overview, created with BioRender, depicts the expression of aquaporin (AQP) in various immune cells.
TABLE 2 Distribution of aquaporins different immune cells
(HPA: humanproteinatlas.org).
AQP Immune cell reference
AQP0 Not detected HPA
AQP1 Lymphocytes (memory T-cells), leucocytes,
activated B and T-lymphocytes
HPA (13,28,29)
AQP2 monocytes HPA
AQP3 Dendritic cells, lymphocytes especially T-cells,
(T-reg
MAIT T-cell
Memory CD4 T-cell
Naive CD4 T-cell
Memory CD8 T-cell
Naive CD8 T-cell) activated B and
T-lymphocytes
HPA (13,28)
AQP4 Not detected HPA
AQP5 Not detected to lymphocytes, dendritic cells
activated B and T-lymphocytes
HPA (13,28)
AQP6 Very low in all immune cells HPA
AQP7 Very low T-cells and B-cells, dendritic
cells, macrophages
HPA (28,29)
AQP7B Very low Basophil Plasmablast HPA
AQP8 Very low T-cells HPA
AQP9 Very high neutrophils, medium monocytes,
leucocytes, macrophages, dendritic cells, HL-
60 cells
HPA (28,29)
AQP10 Very low PBMCs HPA
AQP11 Low in all immune cells HPA
AQP12A Not detected HPA
AQP12B Not detected HPA
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type 8, alpha subunit channels in astrocytes, thereby inhibiting the
Peroxisome proliferator-activated receptor gamma pathway and
providing neuroprotection (42). This upregulation of AQP4 can
be attenuated by dexamethasone, primarily through tumour
necrosis factor alpha (TNF-a) regulation, although the use of
corticosteroids in sepsis remains controversial and is
recommended under certain conditions (43–45).
Elevated ammonia levels in SAE, due to non-hepatic
hyperammonemia, contribute to increased AQP4 expression in
astrocytes, leading to cognitive impairment (46). Fecal microbiota
transplantation in animal models has shown promise in reducing
ammonia levels and improving neurological outcomes by
modulating AQP4 expression via the gut-brain axis (46).
Furthermore, in sepsis-induced delirium (SID), AQP4 expression
in astrocytes is elevated, with exosomes carrying AQP4 proteins
potentially serving as biomarkers for SID (47).
In contrast a rat CLP-model showed that SAE led to impaired
cerebral blood flow, alterations in grey and white matter structure,
and changes in glial cell morphology without causing widespread
blood-brain barrier breakdown, accompanied by reductions in
neuronal cyclooxygenase-2 (COX-2) and aquaporin-4 (AQP4)
expression in cortical regions and increased perivascular COX-2
expression (48).
In experimental models of sepsis, AQP4 deletion attenuates
learning and memory impairment by reducing neuroinflammation,
activating astrocytic autophagy, and downregulating proinflammatory
cytokines (42). It was found that inhibiting LncRNA-5657 with shRNA
reduced neuronal degeneration and inflammatory markers, including
aquaporin 4, metallopeptidase-9, and TNF-alpha levels in the
hippocampus, suggesting its potential protective role against septic
brain injury (49). Additionally, studies investigating endotoxemia-
induced encephalopathy have identified increased AQP4 expression
in the hippocampus, suggesting its involvement in the pathogenesis of
cognitive dysfunction (45,50).
Overall, AQP4 appears to be a crucial mediator in the
pathophysiology of sepsis-associated encephalopathy, involved in
brain edema, cognitive impairment, and potentially serving as a
target for therapeutic intervention in clinical settings.
2.3 Aquaporins in cardiac dysfunction
in sepsis
Cardiac dysfunction in sepsis arises from a combination of
factors including systemic inflammation, cardiodepressive
mediators, endothelial and mitochondrial dysfunction,
hypovolemia, microcirculatory disturbances, bacterial toxins,
oxidative stress, and neurohormonal dysregulation (51). It has
been found that endotoxin administration impairs cardiac
function and induces the expression of gelsolin, AQP1 and iNOS,
with ageing having a negative effect on gelsolin induction and
cardiac performance; in aged mice, increased levels of AQP1,
FIGURE 3
This figure illustrates the updated roles and expressions of aquaporins in differentiated organs in sepsis. (A) AQP4 is upregulated in the brain during
sepsis; (B) AQP1 expression increases in cardiac cells; (C) AQP1, AQP8, and AQP9 are present in bronchiolar epithelial cells, while AQP5 is in alveolar
epithelial cells, with all their expressions reduced in sepsis; (D) AQP2 is localized to the apical and subapical regions of collecting duct principal cells,
with reduced expression in sepsis; (E) AQP8 expression decreases in hepatocytes during sepsis; (F) AQP3 seems to be decreased in intestinal cells.
This figures has been modified and adapted from the following sources (90):and (21).
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iNOS and phosphorylated STAT3 were associated with greater
cardiac dysfunction in response to endotoxic stress (52). In
addition, cardiac expression of AQP1, P53 and P21 was
significantly increased in LPS-treated rats (53). In another study,
reduced H19 and AQP1 expression, coupled with increased miR-
874 levels, were observed in sepsis patients, a lipopolysaccharide
(LPS)-treated mouse model and in cell culture. The results suggest
that H19 acts as a ceRNA for AQP1 by sequestering miR-874,
highlighting its potential as a therapeutic target for mitigating
sepsis-induced myocardial dysfunction (54).In a bacterial
endotoxin-induced mouse model, deletion of aquaporin 9 (AQP9)
improved survival and reduced oxidative stress. A novel AQP9
inhibitor, RG100204, was found to attenuate cardiac dysfunction as
well as renal dysfunction and hepatocellular injury in a cecal
ligation and puncture (CLP) model of sepsis. RG100204
significantly reduced cardiac dysfunction even when administered
3 hours after the onset of sepsis, highlighting AQP9 as a promising
drug target for the treatment of sepsis-induced cardiac dysfunction
(55). In conclusion, it can be stated that AQP1 and, to a lesser
extent, AQP9 appear to be of particular importance in the context of
septic cardiac dysfunction (Figure 3B).
2.4 Aquaporins in lung injury
Acute lung injury (ALI), a severe complication of sepsis often
progressing to acute respiratory distress syndrome (ARDS), is
associated with high in-hospital mortality (56). A number of
aquaporins (AQPs) are expressed in the lungs, with AQP1 and
AQP5 being particularly prevalent in vascular endothelial cells
(Figure 3C), alveolar type I cells, and bronchial epithelial cells. In
contrast, AQP8 and AQP9 are expressed to a lesser extent (57).
In general, AQP1 and AQP5 are of great importance in the
context of regulating fluid transport and inflammation in ALI. Their
expressions and functions vary depending on the specific type and
location of lung injury. These insights into the pathophysiology of
ALI may inform therapeutic strategies aimed at mitigating lung
injury and improving clinical outcomes (58). Furthermore, the
interaction between brain-derived neurotrophic factor (BDNF)
and AQP5 indicates the potential for a novel mechanism that
could mitigate lung damage in septic conditions by inhibiting
excessive autophagy in alveolar epithelial cells (59).
Studies in septic patients have demonstrated increased AQP3
and AQP5 expression in the alveolar septum during diffuse alveolar
damage (60). Conversely, experimental sepsis induced by cecal
ligation puncture (CLP) in rats has been linked to decreased
Aqp5 expression in lung tissue, which can be mitigated by
treatments like emodin and regulated by microRNAs miR-96 and
miR-330 (61–63). Similarly, Aqp1 expression decreases following
exposure to lipopolysaccharide (LPS) in rat lungs, a reduction that
can be counteracted by therapies such as hydrogen-rich saline and
parenteral vitamin C, known for their protective effects in sepsis-
related lung injury (11,64). Experimental ALI models utilising
insults such as LPS, ventilation, hyperoxia and hydrochloric acid
(HCl) have demonstrated an increase in AQP1 expression.
Conversely, mechanical ventilation with high tidal volume has
been observed to result in a reduction in pulmonary AQP1 levels,
which can impact fluid balance and the development of lung
oedema (65). Another study using a CLP-induced sepsis rat
model, myocyte enhancer factor overexpression was found to
alleviate acute lung injury by up-regulating AQP1 expression.
This effect suggests AQP1 modulation as a potential therapeutic
strategy for sepsis-induced ALI (66). In addition, it was
demonstrated that AQP1 expression is decreased in HUVEC cells,
stimulated with the inflammatory factor Tumor Necrosis Factor
Receptor Superfamily, Member 11b (TNFRSF11B) (67).
AQP5, highly expressed in alveolar epithelial cells, is
significantly impaired after prolonged exposure to hyperoxia,
highlighting its role in maintaining water movement and
preventing pulmonary edema (68).
In models of inflammatory pancreatitis, there is a reduction in
the expression of Aqp1 and Aqp5 in the lung, whereas Aqp8 and
Aqp9 remain unaffected. The traditional Chinese medicine Dai-
Huang-Fu-Zi-Tang has been demonstrated to be effective in
upregulating Aqp1 and Aqp5 and in attenuating inflammation in
these scenarios (69).
Further substances have been demonstrated to modulate AQP
expression in lung tissue. Emodin treatment has been shown to
improve sepsis-induced lung pathology by upregulating AQP and
tight junction expression, reducing inflammatory cytokines, and
inhibiting pulmonary apoptosis. These findings suggest that emodin
may have therapeutic potential in the treatment of sepsis-induced
ALI (70). The traditional Chinese formula Da-Cheng-Qi decoction
has been demonstrated to suppress the TLR4/NF-kB signalling
pathway, increase AQP1 and AQP5 protein expression, and inhibit
inflammatory cytokine production. These effects may contribute to
the alleviation of inflammatory reactions in ALI (71).
Dexamethasone pretreatment at various concentrations has been
demonstrated to attenuate lipopolysaccharide (LPS)-induced
suppression of cell proliferation,therebyreducingtheLPS-
induced reduction of aquaporin 5 (AQP5) expression and
apoptosis in neonatal type II alveolar epithelial cells (72).
anshinol treatment in a rat sepsis model has been demonstrated
to significantly increase AQP5 mRNA expression and reduce
inflammatory cytokines IL-6 and TNF-a. This suggests a
protective effect on lung tissue by upregulating AQP5 through the
inhibition of inflammatory pathways (73). Another study explored
the impact of miR-34b-5p on sepsis-induced injury in human renal
tubular epithelial cells, revealing that elevated miR-34b-5p levels in
septic acute kidney injury (AKI) patients correlated with
inflammation and apoptosis through downregulation of AQP2, a
direct target of miR-34b-5p,exacerbatinginjurywhen
overexpressed and mitigated by inhibiting miR-34b-5p or
enhancing AQP2 expression Another study investigated the
influence of miR-34b-5p on sepsis-induced injury in human renal
tubular epithelial cells. The findings indicated that elevated miR-
34b-5p levels in septic acute kidney injury (AKI) patients were
associated with inflammation and apoptosis through the
downregulation of AQP2, a direct target of miR-34b-5p. This
resulted in an exacerbation of injury when miR-34b-5p was
overexpressed and a mitigation of injury when miR-34b-5p was
inhibited or AQP2 expression was enhanced (74). Furthermore, the
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antioxidant Ss-31 was observed to reduce AQP3 expression and
ROS levels, thereby improving vascular permeability and enhancing
the survival of rats with sepsis. These findings indicate that
modulation of AQP3 and inhibition of ROS by Ss-31 may
represent promising strategies for the treatment of sepsis-induced
pulmonary complications (75). In conclusion, the regulation and
expression of aquaporins, particularly AQP1 and AQP5, play a
critical role in fluid transport and inflammatory responses in acute
lung injury (ALI). Variations in AQP expression depending on the
type and location of lung injury provide valuable insights into
potential therapeutic strategies for mitigating sepsis-induced lung
damage. Further research on modulating AQP expression could
lead to improved clinical outcomes in patients with ALI and sepsis.
2.5 Aquaporins in acute kidney injury
Approximately 50% of sepsis patients develop acute kidney
injury (AKI), which is associated with high mortality rates (76).
AQP1 is highly expressed in the kidney and facilitates water
reabsorption in the proximal tubules, the thin descending limb of
Henle, and the descending vasa recta. In contrast, AQP2, AQP3,
and AQP4 are localised to the principal cells of the connecting
tubules and collecting ducts, which are crucial for maintaining body
water homeostasis and urine concentration (77). In AKI mainly
AQP1 and AQP2 seems to be involved (Figure 3D). The expression
of AQP1 is markedly elevated in renal tissue and heart tissue of rats
subjected to LPS-induced AKI, but exhibits a reduction in the lung
and small intestine. This suggests that AQP1 may serve as a
promising novel diagnostic biomarker for septic AKI (53).
Additionally, miR-144-3p upregulation was linked to the
downregulation of aquaporin-1 (AQP1), which may impact renal
function during systemic inflammation induced by
lipopolysaccharide (LPS) (78). AQP1 plays a role in the
protection against LPS-induced acute kidney injury (AKI) by
promoting M2 macrophage polarization, which involves PI3K
activation. AQP1 thus modulates immune responses and
indicates PI3K as a pivotal pathway in AQP1-mediated
macrophage polarization during sepsis-induced AKI (79).
This conclusion is supported by other analyses using an LPS-
induced HK-2 cell model of septic acute kidney injury, which
demonstrated that AQP1 plays a cytoprotective role. The
overexpression of AQP1 in HK-2 cells resulted in the attenuation
of the LPS-induced reduction in cell viability, increase in apoptosis,
and upregulation of proinflammatory cytokines and chemokines.
This was achieved by the inhibition of the p38, p53 and ERK1/2
pathways, which suggests AQP1 as a potential therapeutic target for
sepsis-induced acute kidney injury (80,81).
Further AKI is associated with downregulated Aqp2 expression
through the NF-kB pathway in a CLP mouse model. Pretreatment
with a continuous erythropoietin receptor activator (CERA) or a-
lipoic acid has been demonstrated to preserve Aqp2 expression and
protect against sepsis-induced AKI. Conversely, propofol
pretreatment, but not post-treatment, has been shown to prevent
Aqp2 downregulation and protect renal function during
endotoxemia (21). n a porcine model of sepsis-induced AKI,
treatment with human umbilical cord-derived mesenchymal stem
cells (hUC-MSCs) resulted in a reduction in the expression of Aqp2
in the renal medulla, indicating a protective effect on renal function.
Treatment with hUC-MSCs may protect against endothelial and
tubular injury through the TLR4/NF-kB signalling pathway (82).
2.6 Aquaporins in liver injury
The liver plays many roles in sepsis and is also a target for
sepsis-induced injury. A growing body of evidence from studies
conducted to date indicates that the hepatic inflammatory response,
oxidative stress, microcirculation coagulation dysfunction, and
bacterial translocation play a pivotal role in the occurrence and
development of sepsis-related liver injury (77). Septic shock and its
toxins can cause hypoxic hepatitis, cholestasis due to altered bile
metabolism and acute liver injury (83). In cholestasis,
downregulation of AQP8 by TNF-aafter LPS stimulation reduces
water permeability in hepatocytes, impairing bile formation and
exacerbating cholestasis (84). In addition, AQP8 can modulate
hepatocellular mitochondrial function by altering water transport
(85). AQP1, typically localized to portal venules, hepatic arterioles,
and bile ducts in normal liver and early-stage primary biliary
cirrhosis (PBC), is aberrantly overexpressed in proliferating bile
ductules and arterial capillaries in advanced PBC, potentially
contributing to angiogenesis, fibrosis, and the progression of
portal hypertension (86). In another study, adenoviral delivery of
the human AQP1 gene into rat livers improved LPS-induced
cholestasis by normalising bile flow, biliary bile acid excretion
and serum bile acid levels (Figure 3E). Although it did not alter
protein expression of the canalicular bile salt export pump, hAQP1
expression enhanced its transport activity and restored canalicular
cholesterol content, suggesting a potential therapeutic approach for
sepsis-associated cholestatic diseases (87).
2.7 Sepsis induced intestinal injury
Intestinal injury occurs in sepsis, where the barrier function is
frequently compromised, leading to increased permeability,
bacterial and endotoxin translocation, and further intensification
of the systemic inflammatory response (88). Not much is known
about aquaporins in intestinal injury. In a septic mouse model
induced by cecal ligation and perforation (CLP), sepsis caused
intestinal injury with disrupted mucosal structure, increased
intestinal ischemia–reperfusion injury, increased plasma
diaminooxidase (DAO) and intestinal-type fatty acid-binding
(FABP2) protein levels, and decreased AQP3 and occludin
expression. Oral glycerol administration partially restored
intestinal morphology, decreased intestinal ischemia–reperfusion
injury, decreased DAO and FABP2 levels, upregulated occluding
and AQP3 expression and improved survival compared to
untreated septic mice. These findings suggest a protective role for
AQP3 in sepsis-induced intestinal injury and the potential of
glycerol as a surrogate for AQP3 to improve intestinal barrier
function and survival (89)(Figure 3F).
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3 Polymorphisms in aquaporin genes
In recent years, single-nucleotide polymorphisms (SNPs) in
aquaporin genes have been linked to various pathological
conditions, highlighting their significant clinical value (91–93).
Notably, the -1364 A/C (rs3759129) polymorphism in the
promoter region of the AQP5 gene has been extensively studied
by our group in the context of sepsis (10). The initial investigation
sought to ascertain the correlation between the AQP5 promoter
-1364A/C polymorphism and 30-day survival in patients with
severe sepsis. The findings revealed a notable increase in survival
rates among patients with combined AC/CC genotypes, in
comparison to those with AA genotypes. This observation
remained consistent even after adjusting for various clinical
covariates. The findings emphasize the potential prognostic
significance of AQP5 expression variations in severe sepsis,
underscoring the role of AQP5 channels in influencing patient
outcomes (9). Furthermore, we demonstrated that the C-allele of
the AQP5-1364A/C polymorphism, which is associated with
decreased AQP5 expression and improved outcomes in sepsis, is
linked to higher promoter methylation of AQP5 in neutrophils,
monocytes, and lymphocytes in both septic patients and healthy
controls. Furthermore, decreased AQP5 promoter methylation was
correlated with increased AQP5 expression in cell-line models,
indicating that AQP5 promoter methylation may serve as a
crucial mechanism in genotype-dependent AQP5 expression
regulation. This suggests that AQP5 promoter methylation may
represent a potential target for interventions in sepsis (94). In
patients with sepsis, elevated methylation levels at the cytosine
site nt-937 within the AQP5 promoter are linked to augmented
AQP5 mRNA expression and are predictive of an elevated risk of
mortality within 30 days. This indicates that epigenetic regulation of
AQP5 via NF-kB binding at nt-937 is of pivotal importance in
influencing the outcome of sepsis, thereby underscoring the
potential prognostic significance of AQP5 promoter methylation
in septic patients (95). Aqp5 knockout (KO) mice exhibited
significantly higher survival rates post-LPS injection compared to
wild-type (WT) mice, indicating that Aqp5 deficiency exerts a
protective effect in sepsis. Furthermore, AQP5 expression and the
AQP5 -1364A/C polymorphism were observed to regulate immune
cell migration, with neutrophils from individuals with the AA
genotype demonstrating earlier and more precise migration
compared to those with AC/CC genotypes. This suggests that
AQP5 plays a role in modulating immune responses and survival
outcomes in sepsis (96).
We also examined the association between complications in
septic patients and the AQP5 -1364A/C polymorphism. Here we
investigated the association between the promoter polymorphism
and major adverse kidney events in septic patients, as well as its
impact on 90-day survival. The results demonstrated that
individuals with AC/CC genotypes exhibited a reduced incidence
of major adverse kidney events in comparison to those with AA
genotypes. Furthermore, C-allele carriers demonstrated enhanced
90-day survival rates. Subsequent multiple proportional hazard
analysis substantiated the association between AC/CC genotypes
and a diminished risk of mortality within 90 days, thereby
corroborating the AQP5 -1364A/C polymorphism as an
independent prognostic factor in sepsis, with implications for
precision medicine (97). In acute respiratory distress syndrome
(ARDS) caused by bacterial pneumonia, the AQP5 -1364A/C
promoter polymorphism’s C-allele was linked to reduced
pulmonary inflammation and improved 30-day survival rates,
offering potential insights for characterizing and treating ARDS
on an individualized basis. This finding highlights the impact of
AQP5 genotype on inflammation and prognosis in ARDS,
suggesting a significant advancement in understanding and
managing this condition (98). The association between the AQP5
promoter -1364A/C polymorphism and AKI in patients with
pneumonia-induced acute respiratory distress syndrome (ARDS)
were examined. Results show that while the incidence of AKI upon
admission did not differ between genotypes, by day 30, the AA
genotype had a significantly higher prevalence of AKI compared to
AC/CC genotypes. Moreover, the AA genotype was identified as an
independent risk factor for AKI persistence, indicating that AQP5
genotype may influence AKI development and resolution beyond
fluid balance considerations in ARDS (99).
Furthermore, a polymorphism in the AQP3 gene was examined.
There was an association between AQP3 polymorphism
(rs17553719) and expression with survival outcomes in sepsis
patients. Results showed that the CC genotype was linked to
decreased 30-day survival, higher AQP3 mRNA expression, and
elevated IL-33 concentration, suggesting a potential role of AQP3 in
sepsis prognosis (100).PolymorphismsinAQPgenescould
therefore influence the disease progression in sepsis.
4 Aquaporins in
inflammasome activation
The role of AQPs in inflammasome activation has been
described intensively in other reviews (21,29). The
inflammasome, crucial in the immune response, is found in
macrophages and neutrophil granulocytes and recognizes various
pathogen antigens. The NLRP3 inflammasome, upregulated in
sepsis, triggers the release of IL-1b, dependent on cell pH and
facilitated by aquaporin-mediated water influx in macrophages
(101). The movement of water by AQPs appears to be a pivotal
factor in unifying the activators of the NLRP3 inflammasome. The
absence of AQP1 in a mouse model of acute lung injury resulted in a
reduction in IL-1brelease and neutrophilic inflammation, which
serves to underscore the role of AQPs as a danger signal for NLRP3
activation. AQP3, which is highly expressed in THP-1 cells, plays a
role in the rapid changes in cell volume and the activation of the
inflammasome in response to stimuli such as reswelling, nigericin,
and ATP. The increased expression of AQP3 serves to amplify these
responses, while its peroxiporin activity has been observed to
enhance intracellular ROS and inflammasome activation.
Furthermore, AQP4 resulted in a reduction of NLRP3, caspase-1,
and IL-1bproteins in the treatment group, indicating the
inactivation of the inflammasome (102). Furthermore, the
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absence of AQP5 was observed to facilitate NLRP3 inflammasome
activation via the generation of reactive oxygen species (ROS). The
inhibition of ROS or the blockade of the NLRP3 inflammasome was
observed to markedly diminish the extent of damage and pyroptosis
in AQP5-deficient lacrimal gland epithelial cells (103).
5 Potential role of aquaporins in
immune metabolism
The term “immunometabolism in sepsis”denotes the intricate
interplay between the immune system and the body’s metabolic
processes during the course of sepsis. Immune cells undergo
metabolic alterations during sepsis in order to rapidly provide
energy and materials for defense responses. These involve
increased glycolysis and changes in fatty acid and amino acid
utilization, which occur during the proinflammatory phase of
sepsis (104). Similar to tubular epithelial cells (TECs), immune
cells in sepsis may undergo a profound metabolic transformation,
transitioning from oxidative phosphorylation (OXPHOS) to a
predominance of aerobic glycolysis. Within this metabolic
realignment, the majority of pyruvate generated through
glycolysis avoids mitochondrial entry and is instead converted
into lactate—a process catalyzed by lactate dehydrogenase (LDH).
This strategic metabolic adaptation is crucial, as it supports
increased ATP production through glycolysis to meet the elevated
energy demands imposed by the septic challenge (105). Aquaporins
(AQPs), particularly those involved in glycerol transport, play a
crucial role in enhancing glycolysis during sepsis by ensuring the
availability of key substrates and supporting the increased metabolic
demands of cells. Specifically, aquaglyceroporins such as AQP3,
AQP7, AQP9, and AQP10 facilitate the transport of glycerol across
cell membranes (Table 1). In sepsis, the body’s need for energy
surges, leading to the upregulation of these AQPs. Especially AQP3
and AQP1 seem to be upregulated in immune cells after
inflammatory stimulus (106). It is known that AQP3 and AQP9
can influence gluconeogenesis by transporting glycerol into the cell
(107). The glycerol transported into cells is converted into glycerol-
3-phosphate (G3P) by glycerol kinase, and then into
dihydroxyacetone phosphate (DHAP), an intermediate in the
glycolytic pathway (108)(Figure 4). This process directly feeds
glycerol into glycolysis, enhancing its flux and thereby increasing
ATP production.
Furthermore, during sepsis, hypoxia-inducible factor 1-alpha
(HIF-1a) triggers the upregulation of glucose transporter 1
(GLUT1), enhancing glucose uptake into cells (104). AQP3
supports this process by facilitating the transport of glycerol,
which complements glucose metabolism (Figure 4). Additionally,
elevated levels of O-GlcNAcylation, a post-translational
modification of proteins that occurs during sepsis, further
increase glucose uptake via GLUT1 and regulate glycerol
transport through AQP3. This dual availability of glucose and
glycerol ensures rapid glycolysis, meeting the high energy
demands of immune cells (106,109).
FIGURE 4
Possible role of AQPs in immune metabolism in sepsis: AQP3 and AQP9 facilitate the influx of glycerol into cells, which is converted to glycerol-3-
phosphate by glycerol kinase 2 and then to dihydroxyacetonephosphate (DHAP) by glycerol-3-phosphate dehydrogenase 1. DHAP is incorporated
into glycolysis and could increase glycolysis and lactate production. Lactate leads to increased expression of AQP1. In addition, AQP3 can also
transport H
2
O
2
(reactive oxygen species; ROS), which increases HIF-1 alpha expression and nuclear translocation, which in turn increases AQP3 and
glucose transporter type 1 (GLUT1) expression. Increased glycolysis further increases AQP3 expression via SP1 through the hexosamine
biosynthetic pathway.
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AQP7 also plays a significant role in metabolic regulation by
influencing lipid metabolism and glycerol availability. In sepsis,
increased intracellular glycerol levels or active AQP7 expression
could enhance p38 signaling, which is associated with the
upregulation of glycolysis and nitric oxide production. This
metabolic flexibility might allow immune cells to adapt to the
energy demands of the septic environment (110).
The interaction between glycolysis and glycerol metabolism is
crucial in sepsis. For instance, glycerol processed through glycolysis
can enter the pentose phosphate pathway (PPP), which is important
for producing NADPH and ribose-5-phosphate, essential for
biosynthesis and redox balance in immune cells. AQP1, although
primarily known for water transport, is upregulated by glycolysis
(Figure 4), may also indirectly influence glycolysis by regulating
glucose availability and interacting with other metabolic pathways,
including those involving lactate and hydrogen ion (H+) transport,
which are byproducts of glycolysis (111).
In summary, aquaporins contribute to the increased glycolysis
observed in sepsis by facilitating glycerol transport, supporting
glucose uptake, and interacting with various metabolic signaling
pathways. This enhancement of glycolysis ensures that immune
cells have sufficient energy to respond to infection and maintain
cellular function under the stress of sepsis.
6 Aquaporins as potential drug targets
in sepsis
Aquaporins may be useful drug targets in sepsis. For example,
we recently showed that methazolamide and furosemide reduced
AQP5 expression in REH cells, with methazolamide also reducing
immune cell migration. However, only methazolamide pre-
treatment showed potential to reduce LPS-induced AQP5
expression, suggesting it may be useful in sepsis prophylaxis
(112). AQP9, found in hepatocytes and leukocytes, is being
investigated as a potential target to reduce mortality in septic
shock. Aqp9 knockout (KO) mice showed prolonged survival and
reduced inflammation compared to wild-type (WT) mice after LPS-
induced endotoxic shock. KO mice exhibited reduced production of
pro-inflammatory nitric oxide (NO) and superoxide anion (O2-), as
well as reduced levels of iNOS and COX-2, which was attributed to
impaired NF-kB p65 activation in various tissues. Blocking AQP9
with HTS13286 in FaO cells also prevented LPS-induced
inflammation, suggesting a role for AQP9 in early phases of
endotoxic shock via modulation of NF-kB signalling. These
findings highlight AQP9 as a promising target for the
development of new therapies against endotoxemia (113). In a
study, the novel AQP9 inhibitor RG100204 was shown to normalise
oxidative stress and improve survival in mouse models of sepsis.
RG100204 reduced cardiac and renal dysfunction, decreased
activation of the NLRP3 inflammasome pathway and reduced
myeloperoxidase activity in lung tissue, suggesting that AQP9 is a
potential drug target for polymicrobial sepsis (55). Another study
investigated the role of FGD5-AS1 in sepsis and LPS-induced
inflammation and showed that FGD5-AS1 overexpression
increased AQP1 and decreased miR-133a-3p expression,
subsequently reducing inflammatory cytokines such as TNF-a,
IL-6 and IL-1b. Dual-luciferase reporter and miRNA pull-down
assays confirmed that FGD5-AS1 acts as a competitive endogenous
RNA for miR-133a-3p on AQP1, suggesting that overexpression of
FGD5-AS1 may inhibit the inflammatory response in sepsis (114).
Another study investigated the relationship between AQP1,
miRNA-874 and lncRNA H19 in LPS-induced sepsis. It was
found that H19 and AQP1 expressions decreased while miR-874
expression increased in sepsis samples, mouse models and
cardiomyocytes. H19 acted as a competitive endogenous RNA
(ceRNA) for AQP1 by regulating miR-874, reversing LPS-induced
inflammatory responses and myocardial dysfunction, suggesting
H19 as a potential therapeutic target for sepsis-associated
myocardial dysfunction (54). The development of aquaporin
(AQP) inhibitors faces significant challenges, particularly due to
potential off-target and side effects. Many putative AQP modulators
reported in literature have failed to show consistent activity upon
retesting (115). This inconsistency is often attributed to the
limitations of assays used, such as oocyte swelling or calcein
fluorescence, which are prone to artifacts (116). Apparent
inhibition of osmotic swelling may result from factors unrelated
to AQPs, such as changes in cell volume regulation or the activity of
non-AQP ion or solute transporters. Common inhibitors of ion
transport processes, like bumetanide or acetazolamide, may alter
resting cell volume, further complicating the assessment of true
AQP inhibition (117). The complexity of identifying specific AQP
inhibitors is compounded by the structural characteristics of AQPs
and their high abundance in cell membranes. In some cases,
reported inhibitors, such as loop diuretics or antiepileptics, have
confused the literature due to their lack of specificity and inability to
be confirmed in subsequent studies (115). For example, AER-270, a
claimed selective AQP4 inhibitor, showed only partial inhibition in
mouse and human models, and its effects may be due to its role as
an NF-kB inhibitor rather than directly targeting AQP4 (118,119).
This highlights the need to thoroughly evaluate off-target effects, as
inhibitors may influence pathways beyond AQPs. This underscores
the critical need to better understand these unintended interactions
to develop more selective and effective AQP inhibitors in the future
(120). Further development of AQP-targeted therapeutics requires
well-designed, large-scale functional screens to identify true small-
molecule inhibitors. Additionally, targeting AQP signaling
pathways or intracellular trafficking, as seen with vasopressin
receptor antagonists like vaptans, may offer alternative
therapeutic approaches. Nonetheless, off-target effects remain a
significant concern, underscoring the need for careful validation
in future studies (17,116). It is possible that another potential drug
under investigation, phloretin, may be able to interfere with AQPs.
In vitro studies have shown that inhibition of AQP9 with phloretin
can reduce mortality, inflammatory responses and organ damage in
sepsis models (38).
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Frontiers in Immunology frontiersin.org10
7 Conclusion
AQPs are emerging as crucial players in sepsis, influencing
various organ systems. Their roles in immune cell activation, fluid
regulation, and inflammatory processes make them attractive
therapeutic targets. In sepsis, AQP1, AQP4, AQP5, and AQP9
have been shown to significantly affect organs like the brain,
heart, lungs, kidneys, and liver. For example, AQP4 plays a key
role in SAE by contributing to cerebral edema, while AQP1 and
AQP9 are implicated in myocardial injury and ALI. Modulating
these AQPs shows potential to alleviate organ damage and improve
patient outcomes.
Therapeutic strategies have been developed to target these
proteins. Dexamethasone and traditional Chinese medicines have
shown potential in reducing cardiac and pulmonary damage.
Specific inhibitors such as HTS13286 and RG100204 targeting
AQP9 have demonstrated promise in reducing inflammation,
improving survival, and mitigating organ dysfunction in sepsis
models. These approaches highlight the therapeutic potential of
modulating AQPs in sepsis-related complications like ALI, SAE,
and AKI, which affects around 50% of sepsis patients.
However, the development of AQP inhibitors faces significant
challenges due to potential off-target effects. Many inhibitors
reported in the literature have shown inconsistent activity, often
complicated by nonspecific interactions with other ion transporters
or signaling pathways. Future research must focus on refining these
inhibitors, exploring alternative pathways such as intracellular
trafficking, and conducting large-scale screening to discover more
selective and effective therapeutic options.
In summary, AQPs represent promising biomarkers and
therapeutic targets in sepsis, especially in modulating
inflammation and organ injury in critical systems such as the
brain, heart, lungs, kidneys, and liver. However, the complexity of
their inhibition and the risk of off-target effects necessitate further
investigation into selective therapeutic approaches.
Author contributions
KR: Conceptualization, Project administration, Visualization,
Writing –original draft. MA: Investigation, Resources, Software,
Writing –review & editing.
Funding
The author(s) declare that no financial support was received for
the research, authorship, and/or publication of this article.
Acknowledgments
To improve the quality of the language, DeepL Write (current
version, October 2024) and ChatGPT-4 (October 2024 update)
were used.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated inthis article, or claim that maybe made by its
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