Ablation of Aquaporin-9 Ameliorates the Systemic Inflammatory Response of LPS-Induced Endotoxic Shock in Mouse
Open Access
- 18 February 2021
- Vol. 10 (2), 435
- https://doi.org/10.3390/cells10020435
Abstract
Septic shock is the most severe complication of sepsis, being characterized by a systemic inflammatory response following bacterial infection, leading to multiple organ failure and dramatically high mortality. Aquaporin-9 (AQP9), a membrane channel protein mainly expressed in hepatocytes and leukocytes, has been recently associated with inflammatory and infectious responses, thus triggering strong interest as a potential target for reducing septic shock-dependent mortality. Here, we evaluated whether AQP9 contributes to murine systemic inflammation during endotoxic shock. Wild type (Aqp9+/+; WT) and Aqp9 gene knockout (Aqp9−/−; KO) male mice were submitted to endotoxic shock by i.p. injection of lipopolysaccharide (LPS; 40 mg/kg) and the related survival times were followed during 72 h. The electronic paramagnetic resonance and confocal microscopy were employed to analyze the nitric oxide (NO) and superoxide anion (O2−) production, and the expression of inducible NO-synthase (iNOS) and cyclooxigenase-2 (COX-2), respectively, in the liver, kidney, aorta, heart and lung of the mouse specimens. LPS-treated KO mice survived significantly longer than corresponding WT mice, and 25% of the KO mice fully recovered from the endotoxin treatment. The LPS-injected KO mice showed lower inflammatory NO and O2− productions and reduced iNOS and COX-2 levels through impaired NF-κB p65 activation in the liver, kidney, aorta, and heart as compared to the LPS-treated WT mice. Consistent with these results, the treatment of FaO cells, a rodent hepatoma cell line, with the AQP9 blocker HTS13268 prevented the LPS-induced increase of inflammatory NO and O2−. A role for AQP9 is suggested in the early acute phase of LPS-induced endotoxic shock involving NF-κB signaling. The modulation of AQP9 expression/function may reveal to be useful in developing novel endotoxemia therapeutics.Funding Information
- MIUR (2017J92TM5)
This publication has 77 references indexed in Scilit:
- Chemokine-dependent T cell migration requires aquaporin-3–mediated hydrogen peroxide uptakeThe Journal of Experimental Medicine, 2012
- Aquaporin-9 Protein Is the Primary Route of Hepatocyte Glycerol Uptake for Glycerol Gluconeogenesis in MiceOnline Journal of Public Health Informatics, 2011
- Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signalingProceedings of the National Academy of Sciences of the United States of America, 2010
- Defective glycerol metabolism in aquaporin 9 (AQP9) knockout miceProceedings of the National Academy of Sciences of the United States of America, 2007
- Aquaporin-1 Transports NO Across Cell MembranesHypertension, 2006
- Aquaporin homologues in plants and mammals transport ammoniaFEBS Letters, 2004
- Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic ShockClinical Microbiology Reviews, 2003
- The hepatocyte as a microbial product-responsive cellInnate Immunity, 2001
- Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (Tlr4)The Journal of Experimental Medicine, 1999
- CD14, a Receptor for Complexes of Lipopolysaccharide (LPS) and LPS Binding ProteinScience, 1990