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Zimmermann, S.* ; Mathew, A.* ; Bondareva, O. ; Elwakiel, A.* ; Waldmann, K.* ; Jiang, S.* ; Rana, R.* ; Singh, K.* ; Kohli, S.* ; Shahzad, K.* ; Biemann, R.* ; Roskoden, T.* ; Storsberg, S.D.* ; Mawrin, C.* ; Krügel, U.* ; Bechmann, I.* ; Goldschmidt, J.* ; Sheikh, B. ; Isermann, B.*

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

Kidney Int. 106, 1101-1116 (2024)

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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 K_Ca3.1, and induces p38-MAPK associated IL-1β maturation in microglia. Restoring potassium homeostasis in microglia using a K_Ca3.1-specific inhibitor (TRAM34) improves CKD-triggered cognitive impairment. Likewise, inhibition of the IL-1β receptor 1 (IL-R1) 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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Chronic Kidney Disease ; Cognitive Impairment ; Cytokines ; Microglia-neuron Crosstalk ; Potassium Flux; Nlrp3 Inflammasome; Barrier Breakdown; Injury; Encephalopathy; Contributes; Pathology; Cirrhosis; Deficits; Model

ISSN (print) / ISBN 0085-2538

e-ISSN 1523-1755

Journal Kidney International

Quellenangaben Volume: 106, Issue: 6, Pages: 1101-1116

Publisher Nature Publishing Group

Publishing Place Ste 800, 230 Park Ave, New York, Ny 10169 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)

Grants Medical Faculty of the University of Leipzig
Deutscher Akademischer Austauschdienst (DAAD, German Academic Exchange Service) scholarships
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)