Department of Neurology, University of California, Irvine, CA, USA.
Department of Medicine, Division of Nephrology, University of California, Irvine, CA, USA.
J Neuroinflammation. 2023 Feb 25;20(1):51. doi: 10.1186/s12974-023-02703-2.
Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD.
CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier.
CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood-brain barrier (BBB) by 34% (p < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p < 0.01) and increased sodium fluorescein permeability (p < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p < 0.0001).
CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.
慢性肾脏病（CKD）日益被认为是中风的一个危险因素，但它与脑血管病的确切关系尚不清楚。我们使用 CKD 的体内和体外模型研究了脑小血管疾病的发展。
使用腺嘌呤诱导的肾小管间质性肾炎模型在老年 C57BL/6J 小鼠中产生 CKD。我们使用普鲁士蓝染色分析脑组织学，以检查脑微出血（CMH）的形成，CMH 是小血管疾病的出血成分和 MRI 显示的脑微出血的神经病理学基础。在细胞培养研究中，我们研究了来自健康或 CKD 患者的血清和肠道来源的尿毒症毒素对脑微血管内皮屏障的影响。
在老年 C57BL/6J 小鼠中诱导 CKD，血清肌酐和胱抑素 C 水平显著升高（p<0.0001），而收缩压或舒张压没有升高。CMH 显著增加，与血清肌酐水平呈正相关（Spearman r=0.37，p<0.01）。此外，CKD 使 Iba-1 阳性免疫反应性增加了 51%（p<0.001），诱导了从静止到激活的小胶质细胞表型转变，并使纤维蛋白原穿过血脑屏障（BBB）的外渗增加了 34%（p<0.05）。按性别分层分析，CMH 数量的增加在雄性小鼠中更为明显，这与雄性小鼠比雌性小鼠肌酐升高更为显著相关。用 PLX3397 饮食进行小胶质细胞耗竭可显著减少 CKD 小鼠的 CMH 形成，而不影响血清肌酐水平。CKD 血清孵育可显著降低跨内皮电阻（TEER）（p<0.01），并增加钠荧光素通透性（p<0.05）穿过内皮单层。与对照组相比，尿毒症毒素（即吲哚硫酸、对甲酚硫酸和三甲胺-N-氧化物）与尿素和脂多糖联合使用可导致 TEER 明显下降（p<0.0001）。
CKD 独立于血压促进老年小鼠 CMH 的发展，但与肾功能损害程度直接相关。CKD 的这些作用部分可能由小胶质细胞介导，并与 BBB 损伤有关。后者可能与经典的 CKD 相关的肠道来源的细菌依赖性毒素有关。总的来说，这些发现表明 CKD 在脑小血管疾病的发展中起着重要作用。
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