Abstract
Introduction: Chronic kidney disease (CKD) is increasingly recognized as a risk factor of cerebral microvascular disease, but its association with common neuropathologic changes is not well understood. We investigated the relationship between CKD and development of cerebral microhemorrhages (CMH) in a mouse model of aging. We also examined the effect of CKD on endothelial cell function in an in vitro blood-brain barrier (BBB) model. Methods: CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We performed standard histology using Prussian blue staining to examine CMH formation. Correlations between CMH burden and serum creatinine levels were assessed. In cell culture studies, human brain microvascular endothelial cells (ihBMECs) derived from induced pluripotent stem cell line IMR90-4 were treated with serum from healthy or CKD patient donors for up to 3 days. Transendothelial electrical resistance (TEER) and tracer (sodium fluorescein) permeability across the ihBMEC monolayer were measured to assess the integrity of the in vitro BBB. Results: CKD induction in aged C57BL/6J mice caused a significant increase in both serum creatinine level (0.09±0.01 mg/dL to 0.43±0.03 mg/dL, p<0.001) and CMH number (p<0.05), without alteration of systolic or diastolic blood pressure. Number of CMH was positively correlated with serum creatinine level (r=0.41, p<0.001). Incubation of CKD serum with ihBMECs significantly reduced TEER by 26% (p<0.05) and increased sodium fluorescein permeability by 100% (p<0.01) across the ihBMEC monolayer. Conclusions: Adenine-induced CKD promotes the development of CMH in aged C57BL/6J mice independent of blood pressure, and extent of CMH development is directly proportional to degree of renal insufficiency. Moreover, serum-derived factors in CKD disrupt BBB integrity in vitro. These findings suggest CKD provokes microvascular injury at the capillary level, leading to CMH formation in this model.
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