Aquaporin-9 (AQP9) exerts a role in the early phase of the systemic inflammation of a murine model of endotoxic shock

Abstract

Septic shock is the most severe complication of sepsis, characterized by a systemic inflammatory response following bacterial infection, leading to multiple organ failure and dramatically high mortality. AQP9 is an aquaglyceroporin/peroxiporin mainly expressed in hepatocytes and neutrophils and recently associated with inflammatory and infectious responses. Here, we evaluated whether AQP9 has a role in mouse systemic inflammation during endotoxic shock. Wild-type ( Aqp9+/+; WT) and Aqp9−/− knockout (KO) male mice were submitted to endotoxic shock by i.p. injection of LPS (40 mg/kg) and the related survival times were followed for 72 h. Nitric oxide (NO) and superoxide anion (O2−) production, and the expression of inducible NO‐synthase (iNOS) and cyclooxigenase‐2 (COX‐2) were measured in liver, kidney, aorta, heart and lung of mice. LPS‐treated KO mice survived significantly longer than WT mice, and 25% of the KO mice fully recovered from LPS treatment. The LPS‐injected KO mice had lower inflammatory NO and O2− productions and reduced iNOS and COX‐2 through impaired NF‐κB p65 activation in liver, kidney, aorta, and heart as compared to LPS‐treated WT mice. Treatment of rodent hepatoma FaO cells with the AQP9 blocker HTS13286 prevented the LPS‐induced increase of NO and O2−. AQP9 seems to have a role in the early acute phase of LPS‐induced endotoxic shock likely involving the NF‐κB pathway, potentially through mediating uptake of extracellular H2O2, and PTP-dependent signaling. Support from Italian Government to GC: “Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale 2017” PRIN2017 grant # 2017J92TM5 and “Fondo Integrativo Speciale per la Ricerca 2020”-FISR 2020 CoVAPin grant # FISR2020IP_04051); Support from University of Bari Aldo Moro to GC: grant “Horizon Europe Seeds 2022-2023” NextgenerationEU Programma MUR-Fondo Promozione e Sviluppo-DM 737/2021-Uniba Euroseeds ID #S10. Support from Regione Puglia to PG: “Research for Innovation (REFIN)”, POR Puglia 2014/2020—Asse X—Azione 10.4, UNIBA132-ID #091C54A8. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.