Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury
Acute kidney injury due to renal ischemia-reperfusion injury (IRI) may lead to chronic or end stage kidney disease. A greater understanding of the cellular mechanisms underlying IRI are required to develop therapeutic options aimed at limiting or reversing damage from IRI. Prior work has shown that...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/20/10914 |
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| author | Stephanie M. Mutchler Mahpara Hasan Donald E. Kohan Thomas R. Kleyman Roderick J. Tan |
| author_facet | Stephanie M. Mutchler Mahpara Hasan Donald E. Kohan Thomas R. Kleyman Roderick J. Tan |
| author_sort | Stephanie M. Mutchler |
| collection | DOAJ |
| description | Acute kidney injury due to renal ischemia-reperfusion injury (IRI) may lead to chronic or end stage kidney disease. A greater understanding of the cellular mechanisms underlying IRI are required to develop therapeutic options aimed at limiting or reversing damage from IRI. Prior work has shown that deletion of the α subunit of the epithelial Na+ channel (ENaC) in endothelial cells protects from IRI by increasing the availability of nitric oxide. While canonical ENaCs consist of an α, β, and γ subunit, there is evidence of non-canonical ENaC expression in endothelial cells involving the α subunit. We therefore tested whether the deletion of the γ subunit of ENaC also protects mice from IRI to differentiate between these channel configurations. Mice with endothelial-specific deletion of the γ subunit and control littermates were subjected to unilateral renal artery occlusion followed by 48 h of reperfusion. No significant difference was noted in injury between the two groups as assessed by serum creatinine and blood urea nitrogen, levels of specific kidney injury markers, and histological examination. While deletion of the γ subunit did not alter infiltration of immune cells or cytokine message, it was associated with an increase in levels of total and phosphorylated endothelial nitric oxide synthase (eNOS) in the injured kidneys. Our studies demonstrate that even though deletion of the γ subunit of ENaC may allow for greater activation of eNOS, this is not sufficient to prevent IRI, suggesting the protective effects of α subunit deletion may be due, in part, to other mechanisms. |
| first_indexed | 2024-03-10T06:30:59Z |
| format | Article |
| id | doaj.art-aa44700a1cc94cbaae1d3026b7042ad3 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:30:59Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-aa44700a1cc94cbaae1d3026b7042ad32023-11-22T18:30:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122201091410.3390/ijms222010914Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion InjuryStephanie M. Mutchler0Mahpara Hasan1Donald E. Kohan2Thomas R. Kleyman3Roderick J. Tan4Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USADepartment of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USADepartment of Medicine, University of Utah, Salt Lake City, UT 84112, USADepartments of Medicine, Cell Biology, and Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USADepartment of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USAAcute kidney injury due to renal ischemia-reperfusion injury (IRI) may lead to chronic or end stage kidney disease. A greater understanding of the cellular mechanisms underlying IRI are required to develop therapeutic options aimed at limiting or reversing damage from IRI. Prior work has shown that deletion of the α subunit of the epithelial Na+ channel (ENaC) in endothelial cells protects from IRI by increasing the availability of nitric oxide. While canonical ENaCs consist of an α, β, and γ subunit, there is evidence of non-canonical ENaC expression in endothelial cells involving the α subunit. We therefore tested whether the deletion of the γ subunit of ENaC also protects mice from IRI to differentiate between these channel configurations. Mice with endothelial-specific deletion of the γ subunit and control littermates were subjected to unilateral renal artery occlusion followed by 48 h of reperfusion. No significant difference was noted in injury between the two groups as assessed by serum creatinine and blood urea nitrogen, levels of specific kidney injury markers, and histological examination. While deletion of the γ subunit did not alter infiltration of immune cells or cytokine message, it was associated with an increase in levels of total and phosphorylated endothelial nitric oxide synthase (eNOS) in the injured kidneys. Our studies demonstrate that even though deletion of the γ subunit of ENaC may allow for greater activation of eNOS, this is not sufficient to prevent IRI, suggesting the protective effects of α subunit deletion may be due, in part, to other mechanisms.https://www.mdpi.com/1422-0067/22/20/10914ENaCischemia reperfusion injurynitric oxide |
| spellingShingle | Stephanie M. Mutchler Mahpara Hasan Donald E. Kohan Thomas R. Kleyman Roderick J. Tan Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury International Journal of Molecular Sciences ENaC ischemia reperfusion injury nitric oxide |
| title | Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury |
| title_full | Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury |
| title_fullStr | Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury |
| title_full_unstemmed | Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury |
| title_short | Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury |
| title_sort | deletion of the gamma subunit of enac in endothelial cells does not protect against renal ischemia reperfusion injury |
| topic | ENaC ischemia reperfusion injury nitric oxide |
| url | https://www.mdpi.com/1422-0067/22/20/10914 |
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