The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice
Lynn W Maines, Cecelia L Green, Staci N Keller, Leo R Fitzpatrick, Charles D Smith Apogee Biotechnology Corporation, Hummelstown, PA, USACorrespondence: Charles D Smith, Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA, 17036, USA, Email cdsmith@apogee-biotech.comInt...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2022-11-01
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| Series: | International Journal of Nephrology and Renovascular Disease |
| Subjects: | |
| Online Access: | https://www.dovepress.com/the-sphingosine-kinase-2-inhibitor-opaganib-protects-against-acute-kid-peer-reviewed-fulltext-article-IJNRD |
| _version_ | 1798017754066845696 |
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| author | Maines LW Green CL Keller SN Fitzpatrick LR Smith CD |
| author_facet | Maines LW Green CL Keller SN Fitzpatrick LR Smith CD |
| author_sort | Maines LW |
| collection | DOAJ |
| description | Lynn W Maines, Cecelia L Green, Staci N Keller, Leo R Fitzpatrick, Charles D Smith Apogee Biotechnology Corporation, Hummelstown, PA, USACorrespondence: Charles D Smith, Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA, 17036, USA, Email cdsmith@apogee-biotech.comIntroduction: Acute kidney injury (AKI) is a common multifactorial adverse effect of surgery, circulatory obstruction, sepsis or drug/toxin exposure that often results in morbidity and mortality. Sphingolipid metabolism is a critical regulator of cell survival and pathologic inflammation processes involved in AKI. Opaganib (also known as ABC294640) is a first-in-class experimental drug targeting sphingolipid metabolism that reduces the production and activity of inflammatory cytokines and, therefore, may be effective to prevent and treat AKI.Methods: Murine models of AKI were used to assess the in vivo efficacy of opaganib including ischemia-reperfusion (IR) injury induced by either transient bilateral occlusion of renal blood flow (a moderate model) or nephrectomy followed immediately by occlusion of the contralateral kidney (a severe model) and lipopolysaccharide (LPS)-induced sepsis. Biochemical and histologic assays were used to quantify the effects of oral opaganib treatment on renal damage in these models.Results: Opaganib suppressed the elevations of creatinine and blood urea nitrogen (BUN), as well as granulocyte infiltration into the kidneys, of mice that experienced moderate IR from transient bilateral ligation. Opaganib also markedly decreased these parameters and completely prevented mortality in the severe renal IR model. Additionally, opaganib blunted the elevations of BUN, creatinine and inflammatory cytokines following exposure to LPS.Conclusion: The data support the hypotheses that sphingolipid metabolism is a key mediator of renal inflammatory damage following IR injury and sepsis, and that this can be suppressed by opaganib. Because opaganib has already undergone clinical testing in other diseases (cancer and Covid-19), the present studies support conducting clinical trials with this drug with surgical or septic patients at risk for AKI.Keywords: opaganib, sphingosine kinase, sphingolipid, acute kidney injury, ischemia-reperfusion injury, lipopolysaccharide, sepsis |
| first_indexed | 2024-04-11T16:11:24Z |
| format | Article |
| id | doaj.art-0014741464634bf0a6485073d389366b |
| institution | Directory Open Access Journal |
| issn | 1178-7058 |
| language | English |
| last_indexed | 2024-04-11T16:11:24Z |
| publishDate | 2022-11-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nephrology and Renovascular Disease |
| spelling | doaj.art-0014741464634bf0a6485073d389366b2022-12-22T04:14:39ZengDove Medical PressInternational Journal of Nephrology and Renovascular Disease1178-70582022-11-01Volume 1532333479724The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in MiceMaines LWGreen CLKeller SNFitzpatrick LRSmith CDLynn W Maines, Cecelia L Green, Staci N Keller, Leo R Fitzpatrick, Charles D Smith Apogee Biotechnology Corporation, Hummelstown, PA, USACorrespondence: Charles D Smith, Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA, 17036, USA, Email cdsmith@apogee-biotech.comIntroduction: Acute kidney injury (AKI) is a common multifactorial adverse effect of surgery, circulatory obstruction, sepsis or drug/toxin exposure that often results in morbidity and mortality. Sphingolipid metabolism is a critical regulator of cell survival and pathologic inflammation processes involved in AKI. Opaganib (also known as ABC294640) is a first-in-class experimental drug targeting sphingolipid metabolism that reduces the production and activity of inflammatory cytokines and, therefore, may be effective to prevent and treat AKI.Methods: Murine models of AKI were used to assess the in vivo efficacy of opaganib including ischemia-reperfusion (IR) injury induced by either transient bilateral occlusion of renal blood flow (a moderate model) or nephrectomy followed immediately by occlusion of the contralateral kidney (a severe model) and lipopolysaccharide (LPS)-induced sepsis. Biochemical and histologic assays were used to quantify the effects of oral opaganib treatment on renal damage in these models.Results: Opaganib suppressed the elevations of creatinine and blood urea nitrogen (BUN), as well as granulocyte infiltration into the kidneys, of mice that experienced moderate IR from transient bilateral ligation. Opaganib also markedly decreased these parameters and completely prevented mortality in the severe renal IR model. Additionally, opaganib blunted the elevations of BUN, creatinine and inflammatory cytokines following exposure to LPS.Conclusion: The data support the hypotheses that sphingolipid metabolism is a key mediator of renal inflammatory damage following IR injury and sepsis, and that this can be suppressed by opaganib. Because opaganib has already undergone clinical testing in other diseases (cancer and Covid-19), the present studies support conducting clinical trials with this drug with surgical or septic patients at risk for AKI.Keywords: opaganib, sphingosine kinase, sphingolipid, acute kidney injury, ischemia-reperfusion injury, lipopolysaccharide, sepsishttps://www.dovepress.com/the-sphingosine-kinase-2-inhibitor-opaganib-protects-against-acute-kid-peer-reviewed-fulltext-article-IJNRDopaganibsphingosine kinasesphingolipidacute kidney injuryischemia-reperfusion injurylipopolysaccharidesepsis |
| spellingShingle | Maines LW Green CL Keller SN Fitzpatrick LR Smith CD The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice International Journal of Nephrology and Renovascular Disease opaganib sphingosine kinase sphingolipid acute kidney injury ischemia-reperfusion injury lipopolysaccharide sepsis |
| title | The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice |
| title_full | The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice |
| title_fullStr | The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice |
| title_full_unstemmed | The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice |
| title_short | The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice |
| title_sort | sphingosine kinase 2 inhibitor opaganib protects against acute kidney injury in mice |
| topic | opaganib sphingosine kinase sphingolipid acute kidney injury ischemia-reperfusion injury lipopolysaccharide sepsis |
| url | https://www.dovepress.com/the-sphingosine-kinase-2-inhibitor-opaganib-protects-against-acute-kid-peer-reviewed-fulltext-article-IJNRD |
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