Chronic kidney disease leads to microglial potassium efflux and inflammasome activation in the brain

  1. Zimmermann, Silke
  2. Mathew, Akash
  3. Bondareva, Olga
  4. Elwakiel, Ahmed
  5. Waldmann, Klarina
  6. Jiang, Shihai
  7. Rana, Rajiv
  8. Singh, Kunal
  9. Kohli, Shrey
  10. Shahzad, Khurrum
  11. Biemann, Ronald
  12. Roskoden, Thomas
  13. Storsberg, Silke Diana
  14. Mawrin, Christian
  15. Krügel, Ute
  16. Bechmann, Ingo
  17. Goldschmidt, Jürgen
  18. Sheikh, Bilal N.
  19. Isermann, Berend

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1000 Titel
  • Chronic kidney disease leads to microglial potassium efflux and inflammasome activation in the brain
1000 Autor/in
  1. Zimmermann, Silke |
  2. Mathew, Akash |
  3. Bondareva, Olga |
  4. Elwakiel, Ahmed |
  5. Waldmann, Klarina |
  6. Jiang, Shihai |
  7. Rana, Rajiv |
  8. Singh, Kunal |
  9. Kohli, Shrey |
  10. Shahzad, Khurrum |
  11. Biemann, Ronald |
  12. Roskoden, Thomas |
  13. Storsberg, Silke Diana |
  14. Mawrin, Christian |
  15. Krügel, Ute |
  16. Bechmann, Ingo |
  17. Goldschmidt, Jürgen |
  18. Sheikh, Bilal N. |
  19. Isermann, Berend |
1000 Erscheinungsjahr 2024
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2024-07-30
1000 Erschienen in
1000 Quellenangabe
  • 106(6):1101-1116
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2024
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1016/j.kint.2024.06.028 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Cognitive impairment is common in extracerebral diseases such as chronic kidney disease (CKD). Kidney transplantation reverses cognitive impairment, indicating that cognitive impairment driven by CKD is therapeutically amendable. However, we lack mechanistic insights allowing development of targeted therapies. Using a combination of mouse models (including mice with neuron-specific IL-1R1 deficiency), single cell analyses (single-nuclei RNA-sequencing and single-cell thallium autometallography), human samples and in vitro experiments we demonstrate that microglia activation impairs neuronal potassium homeostasis and cognition in CKD. CKD disrupts the barrier of brain endothelial cells in vitro and the blood-brain barrier in vivo, establishing that the uremic state modifies vascular permeability in the brain. Exposure to uremic conditions impairs calcium homeostasis in microglia, enhances microglial potassium efflux via the calcium-dependent channel KCa3.1, and induces p38-MAPK associated IL-1β maturation in microglia. Restoring potassium homeostasis in microglia using a KCa3.1-specific inhibitor (TRAM34) improves CKD-triggered cognitive impairment. Likewise, inhibition of the IL-1β receptor 1 (IL-1R1) using anakinra or genetically abolishing neuronal IL-1R1 expression in neurons prevent CKD-mediated reduced neuronal potassium turnover and CKD-induced impaired cognition. Accordingly, in CKD mice, impaired cognition can be ameliorated by either preventing microglia activation or inhibiting IL-1R-signaling in neurons. Thus, our data suggest that potassium efflux from microglia triggers their activation, which promotes microglia IL-1β release and IL-1R1-mediated neuronal dysfunction in CKD. Hence, our study provides new mechanistic insight into cognitive impairment in association with CKD and identifies possible new therapeutic approaches.
1000 Sacherschließung
lokal microglia-neuron crosstalk
lokal potassium flux
lokal cognitive impairment
lokal chronic kidney disease
lokal cytokines
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/uri/WmltbWVybWFubiwgU2lsa2U=|https://frl.publisso.de/adhoc/uri/TWF0aGV3LCBBa2FzaA==|https://frl.publisso.de/adhoc/uri/Qm9uZGFyZXZhLCBPbGdh|https://frl.publisso.de/adhoc/uri/RWx3YWtpZWwsIEFobWVk|https://frl.publisso.de/adhoc/uri/V2FsZG1hbm4sIEtsYXJpbmE=|https://frl.publisso.de/adhoc/uri/SmlhbmcsIFNoaWhhaQ==|https://frl.publisso.de/adhoc/uri/UmFuYSwgUmFqaXY=|https://frl.publisso.de/adhoc/uri/U2luZ2gsIEt1bmFs|https://frl.publisso.de/adhoc/uri/S29obGksIFNocmV5|https://frl.publisso.de/adhoc/uri/U2hhaHphZCwgS2h1cnJ1bQ==|https://frl.publisso.de/adhoc/uri/QmllbWFubiwgUm9uYWxk|https://frl.publisso.de/adhoc/uri/Um9za29kZW4sIFRob21hcw==|https://frl.publisso.de/adhoc/uri/U3RvcnNiZXJnLCBTaWxrZSBEaWFuYQ==|https://frl.publisso.de/adhoc/uri/TWF3cmluLCBDaHJpc3RpYW4=|https://frl.publisso.de/adhoc/uri/S3LDvGdlbCwgVXRl|https://frl.publisso.de/adhoc/uri/QmVjaG1hbm4sIEluZ28=|https://frl.publisso.de/adhoc/uri/R29sZHNjaG1pZHQsIErDvHJnZW4=|https://frl.publisso.de/adhoc/uri/U2hlaWtoLCBCaWxhbCBOLg==|https://frl.publisso.de/adhoc/uri/SXNlcm1hbm4sIEJlcmVuZA==
1000 Label
1000 Förderer
  1. Deutsche Forschungsgemeinschaft |
  2. Deutscher Akademischer Austauschdienst |
  3. Medizinische Fakultät, Universität Leipzig |
1000 Fördernummer
  1. IS-67/16-1; IS-67/22-1; IS-67/25-1; IS-67/26-1; SFB854/B26; 361210922/GRK2408/P7&P9; 361210922/GRK2408/P5; SH 849/1-2; KO 5736/1-1; 457240345
  2. -
  3. -
1000 Förderprogramm
  1. -
  2. -
  3. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm -
    1000 Fördernummer IS-67/16-1; IS-67/22-1; IS-67/25-1; IS-67/26-1; SFB854/B26; 361210922/GRK2408/P7&P9; 361210922/GRK2408/P5; SH 849/1-2; KO 5736/1-1; 457240345
  2. 1000 joinedFunding-child
    1000 Förderer Deutscher Akademischer Austauschdienst |
    1000 Förderprogramm -
    1000 Fördernummer -
  3. 1000 joinedFunding-child
    1000 Förderer Medizinische Fakultät, Universität Leipzig |
    1000 Förderprogramm -
    1000 Fördernummer -
1000 Objektart article
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1000 @id frl:6489143.rdf
1000 Erstellt am 2024-11-25T10:47:59.608+0100
1000 Erstellt von 242
1000 beschreibt frl:6489143
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1000 Zuletzt bearbeitet 2025-01-15T11:35:07.862+0100
1000 Objekt bearb. Wed Jan 15 11:34:58 CET 2025
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  1. oai:frl.publisso.de:frl:6489143 |
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