Deficiency of the Two-Pore Potassium Channel KCNK9 Impairs Intestinal Epithelial Cell Survival and Aggravates Dextran Sodium Sulfate-Induced ColitisSummary
Background & Aims: The 2-pore potassium channel subfamily K member 9 (KCNK9) regulates intracellular calcium concentration and thus modulates cell survival and inflammatory signaling pathways. It also was recognized as a risk allele for inflammatory bowel disease. However, it remains unclear...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X22001813 |
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| author | Steffen Pfeuffer Thomas Müntefering Leoni Rolfes Frederike Anne Straeten Susann Eichler Joel Gruchot Vera Dobelmann Tim Prozorovski Boris Görg Mihael Vucur Carsten Berndt Patrick Küry Tobias Ruck Stefan Bittner Dominik Bettenworth Thomas Budde Tom Lüdde Sven G. Meuth |
| author_facet | Steffen Pfeuffer Thomas Müntefering Leoni Rolfes Frederike Anne Straeten Susann Eichler Joel Gruchot Vera Dobelmann Tim Prozorovski Boris Görg Mihael Vucur Carsten Berndt Patrick Küry Tobias Ruck Stefan Bittner Dominik Bettenworth Thomas Budde Tom Lüdde Sven G. Meuth |
| author_sort | Steffen Pfeuffer |
| collection | DOAJ |
| description | Background & Aims: The 2-pore potassium channel subfamily K member 9 (KCNK9) regulates intracellular calcium concentration and thus modulates cell survival and inflammatory signaling pathways. It also was recognized as a risk allele for inflammatory bowel disease. However, it remains unclear whether KCNK9 modulates inflammatory bowel disease via its impact on immune cell function or whether its influence on calcium homeostasis also is relevant in intestinal epithelial cells. Methods: Kcnk9-/- mice were challenged with 3% dextran sulfate sodium (DSS) to induce experimental acute colitis. Primary cultures of intestinal epithelial cells were generated, and expression of potassium channels as well as cytosolic calcium levels and susceptibility to apoptosis were evaluated. Furthermore, we evaluated whether KCNK9 deficiency was compensated by the closely related 2-pore potassium channel KCNK3 in vivo or in vitro. Results: Compared with controls, KCNK9 deficiency or its pharmacologic blockade were associated with aggravated DSS-induced colitis compared with wild-type animals. In the absence of KCNK9, intestinal epithelial cells showed increased intracellular calcium levels and were more prone to mitochondrial damage and caspase-9–dependent apoptosis. We found that expression of KCNK3 was increased in Kcnk9-/- mice but did not prevent apoptosis after DSS exposure. Conversely, increased levels of KCNK9 in Kcnk3-/- mice were associated with an ameliorated course of DSS-induced colitis. Conclusions: KCNK9 enhances mitochondrial stability, reduces apoptosis, und thus supports epithelial cell survival after DSS exposure in vivo and in vitro. Conversely, its increased expression in Kcnk3-/- resulted in less mitochondrial damage and apoptosis and was associated with beneficial outcomes in DSS-induced colitis. |
| first_indexed | 2024-04-13T23:41:35Z |
| format | Article |
| id | doaj.art-66d58bba624540439c1c629a7cb0c453 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-04-13T23:41:35Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-66d58bba624540439c1c629a7cb0c4532022-12-22T02:24:29ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-0114611991211Deficiency of the Two-Pore Potassium Channel KCNK9 Impairs Intestinal Epithelial Cell Survival and Aggravates Dextran Sodium Sulfate-Induced ColitisSummarySteffen Pfeuffer0Thomas Müntefering1Leoni Rolfes2Frederike Anne Straeten3Susann Eichler4Joel Gruchot5Vera Dobelmann6Tim Prozorovski7Boris Görg8Mihael Vucur9Carsten Berndt10Patrick Küry11Tobias Ruck12Stefan Bittner13Dominik Bettenworth14Thomas Budde15Tom Lüdde16Sven G. Meuth17Institute for Translational Neurology and Neurology Clinic, University of Muenster, Muenster, GermanyDepartment of Neurology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyDepartment of Neurology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyInstitute for Translational Neurology and Neurology Clinic, University of Muenster, Muenster, GermanyInstitute for Translational Neurology and Neurology Clinic, University of Muenster, Muenster, GermanyDepartment of Neurology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyDepartment of Neurology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyDepartment of Neurology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyDepartment of Gastroenterology, Hepatology and Infectiology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyDepartment of Gastroenterology, Hepatology and Infectiology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyDepartment of Neurology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyDepartment of Neurology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyDepartment of Neurology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyDepartment of Neurology, University Medical Centre, Johannes Gutenberg University Mainz, Mainz, GermanyDepartment of Medicine B, Gastroenterology and Hepatology, University Hospital Muenster, Muenster, GermanyInstitute of Physiology 1, University of Muenster, Muenster, GermanyDepartment of Gastroenterology, Hepatology and Infectiology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, GermanyDepartment of Neurology, University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Duesseldorf, Germany; Correspondence Address correspondence to: Sven G. Meuth, MD, PhD, Department of Neurology, University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstraße 5, D-40225 Duesseldorf, Germany.Background & Aims: The 2-pore potassium channel subfamily K member 9 (KCNK9) regulates intracellular calcium concentration and thus modulates cell survival and inflammatory signaling pathways. It also was recognized as a risk allele for inflammatory bowel disease. However, it remains unclear whether KCNK9 modulates inflammatory bowel disease via its impact on immune cell function or whether its influence on calcium homeostasis also is relevant in intestinal epithelial cells. Methods: Kcnk9-/- mice were challenged with 3% dextran sulfate sodium (DSS) to induce experimental acute colitis. Primary cultures of intestinal epithelial cells were generated, and expression of potassium channels as well as cytosolic calcium levels and susceptibility to apoptosis were evaluated. Furthermore, we evaluated whether KCNK9 deficiency was compensated by the closely related 2-pore potassium channel KCNK3 in vivo or in vitro. Results: Compared with controls, KCNK9 deficiency or its pharmacologic blockade were associated with aggravated DSS-induced colitis compared with wild-type animals. In the absence of KCNK9, intestinal epithelial cells showed increased intracellular calcium levels and were more prone to mitochondrial damage and caspase-9–dependent apoptosis. We found that expression of KCNK3 was increased in Kcnk9-/- mice but did not prevent apoptosis after DSS exposure. Conversely, increased levels of KCNK9 in Kcnk3-/- mice were associated with an ameliorated course of DSS-induced colitis. Conclusions: KCNK9 enhances mitochondrial stability, reduces apoptosis, und thus supports epithelial cell survival after DSS exposure in vivo and in vitro. Conversely, its increased expression in Kcnk3-/- resulted in less mitochondrial damage and apoptosis and was associated with beneficial outcomes in DSS-induced colitis.http://www.sciencedirect.com/science/article/pii/S2352345X22001813Two-Pore Potassium ChannelsDSS-Induced ColitisCaspase-9 |
| spellingShingle | Steffen Pfeuffer Thomas Müntefering Leoni Rolfes Frederike Anne Straeten Susann Eichler Joel Gruchot Vera Dobelmann Tim Prozorovski Boris Görg Mihael Vucur Carsten Berndt Patrick Küry Tobias Ruck Stefan Bittner Dominik Bettenworth Thomas Budde Tom Lüdde Sven G. Meuth Deficiency of the Two-Pore Potassium Channel KCNK9 Impairs Intestinal Epithelial Cell Survival and Aggravates Dextran Sodium Sulfate-Induced ColitisSummary Cellular and Molecular Gastroenterology and Hepatology Two-Pore Potassium Channels DSS-Induced Colitis Caspase-9 |
| title | Deficiency of the Two-Pore Potassium Channel KCNK9 Impairs Intestinal Epithelial Cell Survival and Aggravates Dextran Sodium Sulfate-Induced ColitisSummary |
| title_full | Deficiency of the Two-Pore Potassium Channel KCNK9 Impairs Intestinal Epithelial Cell Survival and Aggravates Dextran Sodium Sulfate-Induced ColitisSummary |
| title_fullStr | Deficiency of the Two-Pore Potassium Channel KCNK9 Impairs Intestinal Epithelial Cell Survival and Aggravates Dextran Sodium Sulfate-Induced ColitisSummary |
| title_full_unstemmed | Deficiency of the Two-Pore Potassium Channel KCNK9 Impairs Intestinal Epithelial Cell Survival and Aggravates Dextran Sodium Sulfate-Induced ColitisSummary |
| title_short | Deficiency of the Two-Pore Potassium Channel KCNK9 Impairs Intestinal Epithelial Cell Survival and Aggravates Dextran Sodium Sulfate-Induced ColitisSummary |
| title_sort | deficiency of the two pore potassium channel kcnk9 impairs intestinal epithelial cell survival and aggravates dextran sodium sulfate induced colitissummary |
| topic | Two-Pore Potassium Channels DSS-Induced Colitis Caspase-9 |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X22001813 |
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