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ISSN: 2471-2663
Clinical & Medical Biochemistry
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Aquaporins in Sepsis

Katharina Rump* and Michael Adamzik

Clinic for Anaesthesiology, Intensive Care and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum-Langendreer, Ruhr-University Bochum, Bochum, Germany

*Corresponding Author:
Katharina Rump
Clinic for Anesthesiology, Intensive Care and Pain Therapy
University Hospital Knappschaftskrankenhaus Bochum- Langendreer
In der Schornau 55, D-45882 Bochum, D-45882 Bochum, Germany
Tel: (+49) (234) 32-29242
Fax: (+49) (234) 299-3009
E-mail: [email protected]

Received date: May 17, 2017; Accepted date: May 27, 2017; Published date: June 10, 2017

Citation: Rump K, Adamzik M (2017) Aquaporins in Sepsis. Clin Med Biochem 3:126. doi:10.4172/2471-2663.1000126

Copyright: © 2017 Rump K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Sepsis is a common cause of death in intensive care units worldwide. Due to the high complexity of this immunological syndrome development of novel therapeutic strategies is urgent. Promising drug targets or biomarkers may depict aquaporins (AQPs) as they regulate several key mechanisms of sepsis. Here we report on base of the current literature that several AQPs are involved in different physiological processes of sepsis. In immune system, mainly AQPs 3, 5 and 9 seem to be important, as they regulate the migration of different immune cells. Several studies showed that AQP3 is essential for T-cell function and macrophage migration and that AQP5 and AQP9 regulate neutrophil cell migration and impact sepsis survival. Additionally, to the function in immune system AQPs 1 and 5 play a role in sepsis induced lung injury and their downregulation after inflammatory stimulus impair lung injury. By contrast, AQP4 expression is up-regulated during brain inflammation and aggravates brain edema in sepsis. In kidney AQP2 expression is downregulated in sepsis and can cause renal failure. Some studies also suggest a role of AQP1 in cardiac function. In conclusion AQPs are involved in many physiological dysfunctions in sepsis and their expressions are differently regulated. For development of successful therapeutic strategies, more research on genetic regulatory mechanisms of AQPs is needed.


Sepsis; Aquaporins; Biomarkers; Brain edema; Downregulation


Sepsis is one of the most common complications in Intensive Care Units in Germany and the United States, and mortality remains unrestrainable high due to the extreme complexity of this immunological syndrome [1,2]. Predictive biomarkers which characterize this immunological syndrome properly are still missing; hence no individual therapy adapted on the immune status of the unique patient can be conducted. Aquaporins might be convenient biomarkers because they play an important role in inflammation and especially in sepsis as revealed by experimental and association studies [3-6].

Aquaporins (AQPs) are a group of to date 13 identified membrane proteins, which are essential for the regulation of water and salt in- and out flux of the cell. In addition, some AQPs facilitate the passive transport of glycerol and possibly other small solutes such as urea and carbon dioxide through the cell membrane [7]. The water-selective AQPs are involved in many biological functions, including transepithelial fluid transport, cell migration, brain edema and neuroexcitation, whereas the aquaglyceroporins participate in cell proliferation, adipocyte metabolism and epidermal water retention [7]. With this study, we want to elucidate the possible mechanisms of AQPs in sepsis on base of the current literature.

Aquaporins in cell migration

AQPs play an important role in cell migration. The proposed mechanism by which AQPs enhance cell migration is that they are essential for lamellipodia formation as they facilitate actin polymerization/depolymerization at the leading edge of the cell through water influx [8]. As immune cell migration is an essential mechanism in sepsis, AQPs might play a role. Considerable AQPs for immune cell migration might be AQP1, AQP3, AQP5 and AQP9 as they are expressed in activated B and T lymphocytes (AQP1, 3, 5) as well as immature dendritic cells (AQP3, 5) and neutrophils (AQP9) [9,10].

AQP5 seems to be of special interest, because in the past our group demonstrated that the C-allele of the functional AQP5 A (-1364) C promotor polymorphism (rs3759129) is associated with increased survival in severe sepsis but decreased AQP5 expression [3,11]. Recently we could show that Aqp5-knockout (KO) mice show increased survival compared to wildtype mice after LPS induced endotoxemia. Furthermore, AQP5 overexpression caused increased migration of the T-lymphocytic cell line Jurkat. In addition, neutrophil granulocytes from C-allele carriers showed decreased migration compared to A-allele carriers. Therefore, we concluded that the AQP5 genotype and AQP5 protein expression seem to alter neutrophil cell migration and may influence survival in sepsis by altering neutrophil cell migration. Hence AQP5 might be a key protein in inflammation and depict a novel target for developing sepsis therapeutics [12].

Similar to our study Zhu et al. analyzed the effects of AQP3 expression in a sepsis mouse model. They found that mouse resident peritoneal macrophages (mRPMs) express the aquaglyceroporin Aqp3 and to a low extent Aqp7 and Aqp9 in a plasma membrane pattern. In contrast to our study Aqp3-KO mice showed significantly greater mortality than wild-type mice in a model of bacterial peritonitis. In addition, they also showed that Aqp3-KO was accompanied by reduced migration of macrophages [13]. In addition to macrophage function, AQP3 seems also to be crucial for T-cell migration. It is suggested that AQP3-mediated H2O2 uptake is required for chemokine-dependent T cell migration and a sufficient immune response [14].

Similar to the role of AQP5 and AQP3, AQP9 seems to be responsible for neutrophil migration, as Aqp9-KO mice show reduced neutrophil migration to fMLP [15].

Aquaporin expression in immune cells during inflammation

To completely understand the role of AQPs in immune cells in sepsis, it is also important to know how their expression is altered during inflammation. It was demonstrated that in leucocytes of septic patients AQP3 expression is reduced 2.5-fold and that simultaneously AQP1 expression is increased two-fold [16]. In line with this our group showed that AQP1 expression is increased in the monocytic cell line THP-1 after LPS administration, but AQP5 mRNA expression was reduced [17]. In addition, patients with systemic inflammatory response syndrome (SIRS) show increased AQP9 expression in neutrophils compared to healthy controls [18].

Aquaporins in sepsis induced brain inflammation

One devastating complication of sepsis is septic encephalopathy. In this context, aquaporins play an important role, as endotoxemia leads to inflammation in the brain. This causes AQP4 upregulation in the brain associated with brain edema und neutrophil infiltration [19]. Upregulation of AQP4 in brain after LPS exposure can be attenuated by dexamethasone and this mechanism is mainly regulated by TNF-α [20]. In line with this it was demonstrated that systemic administration of lipopolysaccharide increases the expression of AQP4 in the rat anterior pituitary gland [21].

Aquaporins in renal failure

Another common complication in sepsis is acute renal failure (ARF), which is frequently associated with polyuria and urine concentration defects and it increases the mortality rate in sepsis. In a cecal ligation and puncture mouse model for sepsis AQP2 expression is downregulated through NFκB pathway and may therefore cause acute renal failure during sepsis [22].

Another study shows that AQP2 is downregulated after LPS administration in an LPS sepsis model in rats23 and that pretreatment but not post-treatment with propofol prevents AQP2 downregulation and protects renal function during endotoxemia and that this effect may be mediated by regulation of ICAM-1, TNF-α and mediators of apoptosis [23].

Aquaporins in cardiac dysfunction

Another study tested the hypothesis if AQP1 may play a role in cardiac dysfunction during sepsis. They found that AQP1 expression is increased after LPS exposure in cardiac tissue and that this might influence cardiac function [24].

Aquaporins in acute lung injury

Another common complication in sepsis is acute lung injury. Recently it was demonstrated that AQP5 expression is decreased after sepsis induction with CLP in the lung of rats. This effect can be attenuated by emodin [25]. In line with this AQP1 expression is decreased after LPS exposure in rat lungs [6]. As a therapeutic option, it was demonstrated that hydrogen rich saline can be protective in sepsis related lung injury and that it can attenuate the LPS induced reduction of AQP1 and AQP5 expression [5].


The regulatory mechanisms of aquaporins by LPS after endotoxemia seem to be tissue and aquaporin specific, as it can be seen in Table 1 and it was also demonstrated that AQP8 is downregulated in hepatic cells after LPS administration, though TNF-α pathway [26], while AQP9 expression remains unaffected [20,27]. In summary, AQPs protein expressions seem to alter differential pathological mechanisms in sepsis and might be key proteins in inflammation. Elucidating the differential regulatory mechanisms of AQP expression can be helpful for developing novel sepsis therapeutics.

Aquaporin Tissue Regulation during inflammation reference
AQP1 Immune cells ↑ in leukocytes and cell lines (THp-1) 16, 17
Heart ↑ in cardiac cells 24
Lung ↓ in lung tissue after LPS 5, 6
AQP2 kidney ↓ in renal tissue after LPS 22, 23
AQP3 Immune cells ↓ in leukocytes of septic patients 16
AQP4 Brain ↑ in brain and anterior pituitary gland 19, 21
AQP5 Lung ↓ in lung tissue after LPS 25
↓ in THP-1 cells after LPS 17
AQP7 Immune cells ? mouse resident peritoneal macrophages 13
AQP8 Liver ↓ in hepatic cells 26
AQP9 Immune cells ↑ in neutrophils of SIRS patients 18
  ? mouse resident peritoneal macrophages 13

Table 1: Overview of AQP regulation during inflammation


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