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.

中文翻译：

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慢性肾病导致大脑中小胶质细胞钾外流和炎性小体激活


认知障碍在慢性肾病 （CKD） 等脑外疾病中很常见。肾移植可逆转认知障碍，表明 CKD 驱动的认知障碍在治疗上是可以改变的。然而，我们缺乏允许开发靶向治疗的机制见解。使用小鼠模型（包括神经元特异性 IL-1R1 缺陷的小鼠）、单细胞分析 （单核 RNA 测序和单细胞铊自金属造影）、人类样本和 体外实验的组合，我们证明小胶质细胞活化会损害 CKD 中的神经元钾稳态和认知。CKD 在体外破坏脑内皮细胞 屏障，在体内破坏血脑屏障 ，确定尿毒症状态改变大脑中的血管通透性。暴露于尿毒症条件下会损害小胶质细胞中的钙稳态，通过钙依赖性通道 KCa3.1 增强小胶质细胞钾外流，并诱导小胶质细胞中 p38-MAPK 相关的 IL-1β 成熟。使用 KCa3.1 特异性抑制剂 （TRAM34） 恢复小胶质细胞中的钾稳态可改善 CKD 触发的认知障碍。同样，使用阿那白滞素抑制 IL-1β 受体 1 （IL-1R1） 或基因消除神经元中神经元 IL-1R1 的表达可防止 CKD 介导的神经元钾周转减少和 CKD 诱导的认知障碍。因此，在 CKD 小鼠中，可以通过阻止小胶质细胞激活或抑制神经元中的 IL-1R 信号传导来改善认知受损。因此，我们的数据表明，小胶质细胞的钾外流触发了它们的激活，从而促进了小胶质细胞 IL-1β 的释放和 IL-1R1 介导的 CKD 神经元功能障碍。 因此，我们的研究为与 CKD 相关的认知障碍提供了新的机制见解，并确定了可能的新治疗方法。