Chronic Kidney Disease Increases Cerebral Microbleeds in Mouse and Man
Chronic Kidney Disease Increases Cerebral Microbleeds in Mouse and Man
复制标题
DOI：
10.1007/s12975-019-00698-8
复制
发表时间：
2020-02-01
影响因子：
6.9
通讯作者：
Fisher, Mark
中科院分区：
文献类型：
--
作者：
Lau, Wei Ling;Nunes, Ane C. F.;Fisher, Mark
脑微出血在慢性肾脏病（CKD）中增加，其存在增加了认知能力下降和中风的风险。我们在小鼠和细胞培养模型中研究了CKD和脑微出血（微出血的神经病理学底物）之间的相互作用，并研究了人类连续脑成像中微出血负荷的进展。小鼠研究：研究了两种CKD模型：腺嘌呤诱导的肾小管间质性肾炎和手术5/6肾切除术。细胞培养研究：bEnd.3使小鼠脑内皮细胞生长至汇合，并在暴露于5-15%人尿毒症血清或增加浓度的尿素后测量单层完整性。人体研究：在对照、透析前CKD和透析患者的系列MRI上评价脑微出血的进展。在5/6肾切除模型中，CKD小鼠的微血管扩张增加2-2.5倍，与高血压无关。CKD动物中IgG染色增加，与血脑屏障通透性增加一致。用尿毒症血清或升高的尿素孵育bEnd.3细胞产生跨内皮电阻的剂量依赖性下降。尿素升高诱导肌动蛋白细胞骨架紊乱和claudin-5表达降低。在人类受试者中，两个CKD队列的微出血患病率均为50%，而年龄匹配的对照组为10%。透析队列中更多患者在1.5年后的随访MRI中微出血增加。CKD破坏血脑屏障，增加小鼠的脑微出血和人类的微出血。升高的尿素改变了培养的内皮细胞中的肌动蛋白细胞骨架和紧密连接蛋白，这表明这些机制解释了（至少部分）在动物和人体研究中观察到的微出血和微出血。
Brain microbleeds are increased in chronic kidney disease (CKD) and their presence increases risk of cognitive decline and stroke. We examined the interaction between CKD and brain microhemorrhages (the neuropathological substrate of microbleeds) in mouse and cell culture models and studied progression of microbleed burden on serial brain imaging from humans. Mouse studies: Two CKD models were investigated: adenine-induced tubulointerstitial nephritis and surgical 5/6 nephrectomy. Cell culture studies: bEnd.3 mouse brain endothelial cells were grown to confluence, and monolayer integrity was measured after exposure to 5-15% human uremic serum or increasing concentrations of urea. Human studies: Progression of brain microbleeds was evaluated on serial MRI from control, pre-dialysis CKD, and dialysis patients. Microhemorrhages were increased 2-2.5-fold in mice with CKD independent of higher blood pressure in the 5/6 nephrectomy model. IgG staining was increased in CKD animals, consistent with increased blood-brain barrier permeability. Incubation of bEnd.3 cells with uremic serum or elevated urea produced a dose-dependent drop in trans-endothelial electrical resistance. Elevated urea induced actin cytoskeleton derangements and decreased claudin-5 expression. In human subjects, prevalence of microbleeds was 50% in both CKD cohorts compared with 10% in age-matched controls. More patients in the dialysis cohort had increased microbleeds on follow-up MRI after 1.5 years. CKD disrupts the blood-brain barrier and increases brain microhemorrhages in mice and microbleeds in humans. Elevated urea alters the actin cytoskeleton and tight junction proteins in cultured endothelial cells, suggesting that these mechanisms explain (at least in part) the microhemorrhages and microbleeds observed in the animal and human studies.