Chronic kidney disease leads to microglial potassium efflux and inflammasome activation in the brain DOI Creative Commons
Silke Zimmermann, Akash Mathew, Olga Bondareva

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Июнь 6, 2024

Abstract Cognitive impairment is common in peripheral diseases such as chronic kidney disease (CKD). Kidney transplantation reverses cognitive impairment, indicating that driven by CKD therapeutically amendable. Yet, we lack mechanistic insights allowing targeted therapies. Using a combination of mouse models (including mice with neuron-specific IL-1R1 deficiency), single cell analyses (single nuclei RNA sequencing and thallium automethallography), human samples in vitro experiments demonstrate microglia activation impairs neuronal potassium homeostasis cognition CKD. conditions disrupt the barrier brain endothelial cells blood-brain vivo, establishing are exposed to uremic conditions. Exposure calcium microglia, enhances microglial (K+) efflux via calcium-dependent channel KCa3.1, induces p38-MAPK associated IL-1β maturation microglia. Restoring K+ using KCa3.1-specific inhibitor (TRAM34) improves CKD-triggered impairment. Likewise, inhibition receptor 1 (IL-1R1) anakinra or genetically abolishing expression neurons prevent CKD-mediated reduced turnover CKD-induced impaired cognition. Thus, can be ameliorated either preventing inhibiting IL-1R-signaling neurons. These data suggest from triggers their activation, which promotes release IL-1R1-mediated dysfunction This study provides new insight into association identifies possible therapeutic approaches.

Язык: Английский

Chronic kidney disease leads to microglial potassium efflux and inflammasome activation in the brain DOI Creative Commons
Silke Zimmermann, Akash Mathew, Olga Bondareva

и другие.

Kidney International, Год журнала: 2024, Номер 106(6), С. 1101 - 1116

Опубликована: Июль 30, 2024

Cognitive impairment is common in extracerebral diseases such as chronic kidney disease (CKD). Kidney transplantation reverses cognitive impairment, indicating that driven by CKD therapeutically amendable. However, we lack mechanistic insights allowing development of targeted therapies. Using a combination mouse models (including mice with neuron-specific IL-1R1 deficiency), single cell analyses (single nuclei RNA sequencing and thallium autometallography), human samples vitro experiments demonstrate microglia activation impairs neuronal potassium homeostasis cognition CKD. disrupts the barrier brain endothelial cells blood-brain vivo, establishing uremic state modifies vascular permeability brain. Exposure to conditions calcium microglia, enhances microglial efflux via calcium-dependent channel KCa3.1, induces p38-MAPK associated IL-1β maturation microglia. Restoring using KCa3.1-specific inhibitor (TRAM34) improves CKD-triggered impairment. Likewise, inhibition receptor 1 (IL-R1) anakinra or genetically abolishing expression neurons prevent CKD-mediated reduced turnover CKD-induced impaired cognition. Accordingly, mice, can be ameliorated either preventing inhibiting IL-1R-signaling neurons. Thus, our data suggest from triggers their activation, which promotes release IL-1R1-mediated dysfunction Hence, study provides new insight into association identifies possible therapeutic approaches.

Язык: Английский

Процитировано

9
Chronic kidney disease leads to microglial potassium efflux and inflammasome activation in the brain DOI Creative Commons
Silke Zimmermann, Akash Mathew, Olga Bondareva

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Июнь 6, 2024

Abstract Cognitive impairment is common in peripheral diseases such as chronic kidney disease (CKD). Kidney transplantation reverses cognitive impairment, indicating that driven by CKD therapeutically amendable. Yet, we lack mechanistic insights allowing targeted therapies. Using a combination of mouse models (including mice with neuron-specific IL-1R1 deficiency), single cell analyses (single nuclei RNA sequencing and thallium automethallography), human samples in vitro experiments demonstrate microglia activation impairs neuronal potassium homeostasis cognition CKD. conditions disrupt the barrier brain endothelial cells blood-brain vivo, establishing are exposed to uremic conditions. Exposure calcium microglia, enhances microglial (K+) efflux via calcium-dependent channel KCa3.1, induces p38-MAPK associated IL-1β maturation microglia. Restoring K+ using KCa3.1-specific inhibitor (TRAM34) improves CKD-triggered impairment. Likewise, inhibition receptor 1 (IL-1R1) anakinra or genetically abolishing expression neurons prevent CKD-mediated reduced turnover CKD-induced impaired cognition. Thus, can be ameliorated either preventing inhibiting IL-1R-signaling neurons. These data suggest from triggers their activation, which promotes release IL-1R1-mediated dysfunction This study provides new insight into association identifies possible therapeutic approaches.

Язык: Английский

Процитировано

0