AQP5-1364A/C polymorphism and the AQP5 expression influence sepsis survival and immune cell migration: a prospective laboratory and patient study

Abstract

BackgroundThe C-allele of the aquaporin (AQP5) -1364A/C polymorphism is associated with decreased AQP5 expression but increased 30-day survival in patients with severe sepsis. AQP5 expression might affect survival via an impact on cell migration. Consequently, we tested the hypothesis that (1) Aqp5 knockout (KO) compared to wild type (WT) mice show an increased survival following lipopolysaccharide (LPS) administration, and that (2) AQP5 expression and the AQP5 -1364A/C polymorphism alters immune cell migration.MethodsWe investigated Aqp5-KO and wild type mice after intraperitoneal injection of either E.coli lipopolysaccharide (LPS, serotype O127:B8, 20 mg/kg) or saline. Furthermore, neutrophils of volunteers with the AA-AQP5 or AC/CC-AQP5- genotype were incubated with 10−8 M Chemotactic peptide (fMLP) and their migration was assessed by a filter migration assay. Additionally, AQP5 expression after fMLP incubation was analyzed by RT-PCR and Western blot. Moreover, migration of AQP5 overexpressing Jurkat cells was studied after SDF-1α-stimulation. We used exact Wilcoxon–Mann–Whitney tests; exact Wilcoxon signed-rank tests and the Kaplan–Meier estimator for statistical analysis.ResultsFifty-six percent of Aqp5-KO but only 22% of WT mice survived following LPS-injection. WT mice showed increased neutrophil migration into peritoneum and lung compared to Aqp5-KO mice. Target-oriented migration of neutrophils was seen after 0.5 h in AA-genotype cells but only after 1.5 h in AC/CC-genotype cells, with a threefold lower migrating cell count. AQP5 overexpressing Jurkat cells showed a 2.4 times stronger migration compared to native Jurkat cells.ConclusionThe AQP5 genotype may influence survival following LPS by altering neutrophil cell migration. Trial registration DRKS00010437. Retrospectively registered 26 April 2016Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1079-2) contains supplementary material, which is available to authorized users.

Major Adverse Kidney Events Are Associated with the Aquaporin 5 -1364A/C Promoter Polymorphism in Sepsis: A Prospective Validation Study

“…This, in turn, may orchestrate deleterious effects on the kidney, e.g., by renal capillary plugging and micro-thrombi [33]. Certainly, AQP5 significantly impacts upon key mechanisms of inflammation that prevail in sepsis, including immune cell migration and proliferation [13,14]. AQP5 expression facilitates cell movement by transient formation of membrane protrusions via water entry (lamellipodia and membrane ruffles) [14], and target-oriented human neutrophil migration is faster and more frequent with increased AQP5 expression in the AA genotype of the AQP5 -1364A/C SNP [13].…”

“…Certainly, AQP5 significantly impacts upon key mechanisms of inflammation that prevail in sepsis, including immune cell migration and proliferation [13,14]. AQP5 expression facilitates cell movement by transient formation of membrane protrusions via water entry (lamellipodia and membrane ruffles) [14], and target-oriented human neutrophil migration is faster and more frequent with increased AQP5 expression in the AA genotype of the AQP5 -1364A/C SNP [13]. Since C-allele carriers are associated with a lower AQP5 expression in sepsis compared to the AA genotypes [16], the AC/CC genotypes may confer an altered immune response.…”

“…Genetic factors have been proposed to contribute to interindividual differences of susceptibility to and recovery from AKI relevantly [10]. A promising candidate gene for investigation of sepsis-associated AKI is the water channel Aquaporin 5 (AQP5) since AQP5 is not only associated with transcellular and renal fluid transport [11], but also with cell proliferation [12] and key mechanisms of inflammation [13,14]. In humans, an altered AQP5 expression is linked to a common single nucleotide polymorphism (SNP; -1364A/C; rs3759129) in the AQP5 gene promoter.…”

NFKB1 Promoter DNA from nt+402 to nt+99 Is Hypomethylated in Different Human Immune Cells

“…For this purpose, cells were incubated with 50 μM 5-Aza-2′-deoxycytidine (ADC) for three days and, after culture medium change, with 10 μM ADC for an additional three days. Our previous studies indicated that a seven day incubation period is required for efficient demethylation of promoters [ 9 ]. In addition, we investigated the impact of bacterial cell wall components on NFKB1 promoter methylation.…”

P38 mitogen-activated protein kinase inhibition attenuates mechanical stress induced lung injury via up-regulating AQP5 expression in rats

“…AQP5 is mainly located on the membrane of type I alveolar epithelial cells and has the function of maintaining the water balance of cells [8][9][10]. Studies have shown that AQP5 is associated with different diseases [11][12][13]. For example, it has been reported that AQP5 plays an important role in the elimination of extravascular lung water, and the increase of AQP5 can contribute to lung injury in patients with sepsis [10].…”