RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis
Sepsis is caused by systemic infection and is a major health concern as it is the primary cause of death from infection. It is the leading cause of mortality worldwide and there are no specific effective treatments for sepsis. Gene deletion of the neutral solute channel Aquaporin 9 (AQP9) normalizes...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-06-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.900906/full |
| _version_ | 1818212629742616576 |
|---|---|
| author | Shireen Mohammad Caroline E. O’Riordan Chiara Verra Eleonora Aimaretti Gustavo Ferreira Alves Klaus Dreisch Johan Evenäs Patrizia Gena Angela Tesse Michael Rützler Michael Rützler Massimo Collino Giuseppe Calamita Christoph Thiemermann |
| author_facet | Shireen Mohammad Caroline E. O’Riordan Chiara Verra Eleonora Aimaretti Gustavo Ferreira Alves Klaus Dreisch Johan Evenäs Patrizia Gena Angela Tesse Michael Rützler Michael Rützler Massimo Collino Giuseppe Calamita Christoph Thiemermann |
| author_sort | Shireen Mohammad |
| collection | DOAJ |
| description | Sepsis is caused by systemic infection and is a major health concern as it is the primary cause of death from infection. It is the leading cause of mortality worldwide and there are no specific effective treatments for sepsis. Gene deletion of the neutral solute channel Aquaporin 9 (AQP9) normalizes oxidative stress and improves survival in a bacterial endotoxin induced mouse model of sepsis. In this study we described the initial characterization and effects of a novel small molecule AQP9 inhibitor, RG100204, in a cecal ligation and puncture (CLP) induced model of polymicrobial infection. In vitro, RG100204 blocked mouse AQP9 H2O2 permeability in an ectopic CHO cell expression system and abolished the LPS induced increase in superoxide anion and nitric oxide in FaO hepatoma cells. Pre-treatment of CLP-mice with RG100204 (25 mg/kg p.o. before CLP and then again at 8 h after CLP) attenuated the hypothermia, cardiac dysfunction (systolic and diastolic), renal dysfunction and hepatocellular injury caused by CLP-induced sepsis. Post-treatment of CLP-mice with RG100204 also attenuated the cardiac dysfunction (systolic and diastolic), the renal dysfunction caused by CLP-induced sepsis, but did not significantly reduce the liver injury or hypothermia. The most striking finding was that oral administration of RG100204 as late as 3 h after the onset of polymicrobial sepsis attenuated the cardiac and renal dysfunction caused by severe sepsis. Immunoblot quantification demonstrated that RG100204 reduced activation of the NLRP3 inflammasome pathway. Moreover, myeloperoxidase activity in RG100204 treated lung tissue was reduced. Together these results indicate that AQP9 may be a novel drug target in polymicrobial sepsis. |
| first_indexed | 2024-12-12T05:51:26Z |
| format | Article |
| id | doaj.art-1a16582065b24e0894afbde23cc9667f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T05:51:26Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1a16582065b24e0894afbde23cc9667f2022-12-22T00:35:40ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-06-011310.3389/fimmu.2022.900906900906RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine SepsisShireen Mohammad0Caroline E. O’Riordan1Chiara Verra2Eleonora Aimaretti3Gustavo Ferreira Alves4Klaus Dreisch5Johan Evenäs6Patrizia Gena7Angela Tesse8Michael Rützler9Michael Rützler10Massimo Collino11Giuseppe Calamita12Christoph Thiemermann13William Harvey Research Institute, Queen Mary University of London, London, United KingdomWilliam Harvey Research Institute, Queen Mary University of London, London, United KingdomWilliam Harvey Research Institute, Queen Mary University of London, London, United KingdomDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyDepartment of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, ItalyRed Glead Discovery Akiebolag (AB), Lund, SwedenRed Glead Discovery Akiebolag (AB), Lund, SwedenDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari “Aldo Moro”, Bari, ItalyNantes Université, Instite National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Rescherche Scientifique (CNRS), l’institut du Thorax, Nantes, FranceDepartment of Biochemistry and Structural Biology, Lund University, Lund, SwedenApoglyx Akiebolag (AB), Lund, SwedenDepartment of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, ItalyDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari “Aldo Moro”, Bari, ItalyWilliam Harvey Research Institute, Queen Mary University of London, London, United KingdomSepsis is caused by systemic infection and is a major health concern as it is the primary cause of death from infection. It is the leading cause of mortality worldwide and there are no specific effective treatments for sepsis. Gene deletion of the neutral solute channel Aquaporin 9 (AQP9) normalizes oxidative stress and improves survival in a bacterial endotoxin induced mouse model of sepsis. In this study we described the initial characterization and effects of a novel small molecule AQP9 inhibitor, RG100204, in a cecal ligation and puncture (CLP) induced model of polymicrobial infection. In vitro, RG100204 blocked mouse AQP9 H2O2 permeability in an ectopic CHO cell expression system and abolished the LPS induced increase in superoxide anion and nitric oxide in FaO hepatoma cells. Pre-treatment of CLP-mice with RG100204 (25 mg/kg p.o. before CLP and then again at 8 h after CLP) attenuated the hypothermia, cardiac dysfunction (systolic and diastolic), renal dysfunction and hepatocellular injury caused by CLP-induced sepsis. Post-treatment of CLP-mice with RG100204 also attenuated the cardiac dysfunction (systolic and diastolic), the renal dysfunction caused by CLP-induced sepsis, but did not significantly reduce the liver injury or hypothermia. The most striking finding was that oral administration of RG100204 as late as 3 h after the onset of polymicrobial sepsis attenuated the cardiac and renal dysfunction caused by severe sepsis. Immunoblot quantification demonstrated that RG100204 reduced activation of the NLRP3 inflammasome pathway. Moreover, myeloperoxidase activity in RG100204 treated lung tissue was reduced. Together these results indicate that AQP9 may be a novel drug target in polymicrobial sepsis.https://www.frontiersin.org/articles/10.3389/fimmu.2022.900906/fullaquaporin (AQP)sepsiscecal ligation and punctureinflammationmultiple organ failure |
| spellingShingle | Shireen Mohammad Caroline E. O’Riordan Chiara Verra Eleonora Aimaretti Gustavo Ferreira Alves Klaus Dreisch Johan Evenäs Patrizia Gena Angela Tesse Michael Rützler Michael Rützler Massimo Collino Giuseppe Calamita Christoph Thiemermann RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis Frontiers in Immunology aquaporin (AQP) sepsis cecal ligation and puncture inflammation multiple organ failure |
| title | RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis |
| title_full | RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis |
| title_fullStr | RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis |
| title_full_unstemmed | RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis |
| title_short | RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis |
| title_sort | rg100204 a novel aquaporin 9 inhibitor reduces septic cardiomyopathy and multiple organ failure in murine sepsis |
| topic | aquaporin (AQP) sepsis cecal ligation and puncture inflammation multiple organ failure |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.900906/full |
| work_keys_str_mv | AT shireenmohammad rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT carolineeoriordan rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT chiaraverra rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT eleonoraaimaretti rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT gustavoferreiraalves rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT klausdreisch rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT johanevenas rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT patriziagena rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT angelatesse rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT michaelrutzler rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT michaelrutzler rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT massimocollino rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT giuseppecalamita rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis AT christophthiemermann rg100204anovelaquaporin9inhibitorreducessepticcardiomyopathyandmultipleorganfailureinmurinesepsis |