Prostaglandin transporter PGT as a new pharmacological target in the prevention of inflammatory cytokine-induced injury in renal proximal tubular HK-2 cells

• Published in: Life sciences (1973) 2023-01, Vol.313, p.121260-121260, Article 121260
• Main Authors: Yago-Ibáñez, Julia, Muñoz-Moreno, Laura, Gallego-Tamayo, Beatriz, Lucio-Cazaña, Francisco Javier, Fernández-Martínez, Ana Belén
• Format: Article
• Language: English
• Subjects: Acute kidney injury; Cytokines; Epithelial Cells; Inflammation; Inflammatory cytokines; Kidney; Kidney Tubules, Proximal; Prostaglandin E2; Prostaglandin transporter; Prostaglandins; Proximal tubular cells
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2022.121260

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. 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. 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. These results indicate that PGT-, iPGE2-dependent mechanisms mediate inflammatory cytokine-induced 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.