Prostaglandin transporter PGT as a new pharmacological target in the prevention of inflammatory cytokine-induced injury in renal proximal tubular HK-2 cells
Entity
UAM. Departamento de BiologíaPublisher
ElsevierDate
2022-12-05Citation
10.1016/j.lfs.2022.121260
Life Sciences 313 (2023): 121260
ISSN
0024-3205DOI
10.1016/j.lfs.2022.121260Funded by
This work was supported by a grant COVID-19 2021 2020/00003/ 016/001/009 from the Universidad de Alcala and a grant Ayudas a la Investigacion ´ Departamento de Biología UAM. This research is part of the project on COVID-19 and diabetes (REACT UE-CM2021-02) funded by the Community of Madrid in agreement with the University of Alcala, ´ and co-funded with REACT-EU resources from the European Regional Development Fund “A way to make Europe”Project
Gobierno de España. REACT UE-CM2021-02Editor's Version
https://doi.org/10.1016/j.lfs.2022.121260Subjects
Acute kidney injury; Inflammation; Inflammatory cytokines; Prostaglandin E2; Prostaglandin transporter; Proximal tubular cells; Biología y Biomedicina / BiologíaRights
© 2022 The AuthorsEsta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Aims: Inflammatory cytokines contribute to proximal tubular cell (PTC) injury leading to the deterioration of
renal function and acute kidney injury (AKI) development. They also stimulate cyclo‑oxygenase-2 (COX-2)-
dependent production and release to the extracellular medium of prostaglandin E2 (PGE2), a mediator of PTC
injury. However, in several settings PGE2 re-uptake by prostaglandin transporter (PGT) is critical for PGE2-
mediated PTC injury. Here we investigated several deleterious effects of pro-inflammatory cytokines in PTC and
their prevention by PGT targeting.
Main methods: In human kidney-2 (HK-2) PTC exposed to an inflammatory cytokine cocktail, consisting of interleukins (IL) IL-1α, IL-1β and IL-2, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), were determined
the changes in several parameters related to PTC injury, their dependency on PGE2 (through modulation by
antagonists of PGE2 receptors) and the preventive effect of PGT inhibitor bromosulfophthalein.
Key findings: The cytokine cocktail induced a COX-2-dependent increase in intracellular PGE2 (iPGE2) and cell
death, together to a decrease in cell number and cell proliferation. There was also loss of adherent cells to
collagen IV, changes in actin cytoskeleton and loss of monolayer integrity, together to an increase in paracellular
permeability. All the changes were sensitive to antagonist of PGE2 receptors AH6809 and were fully prevented by
bromosulfophthalein.
Significance: These results indicate that PGT-, iPGE2-dependent mechanisms mediate inflammatory cytokineinduced HK-2 cell injury and suggest that treatment with PGT inhibitors might help to prevent AKI induced
by sepsis, renal ischemia/reperfusion and other pathological conditions in which inflammatory cytokines
contribute to PTC damage
Files in this item
Google Scholar:Yago Ibáñez, Julia
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Muñoz Moreno, Laura
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Gallego Tamayo, Beatriz
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Lucio Cazaña, Francisco Javier
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Fernández Martínez, Ana Belén
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