Studying the spatial neuroinflammatory profile and BBB disruption in a kidney injury mouse model
Summary
Chronic Kidney Disease (CKD) is a prevalent condition characterized by progressive kidney
dysfunction, leading to systemic retention of toxic metabolites called Protein-Bound Uremic
Toxins (PBUTs). CKD patients face significantly higher risk of experiencing neurological
complications, such as cognitive impairment and cerebrovascular disease. We hypothesize
that understanding the pathological role of PBUT accumulation in neuroinflammation and
Blood-Brain Barrier (BBB) dysfunction phenomena is crucial to elucidate CKD-associated
neurological pathologies. In this study, we used a mouse model of kidney injury induced by
renal ischemic reperfusion injury (rIRI) as a proxy for CKD, we investigated the applicability of
the model, and we established a methodological framework to study the potential impact of
PBUTs on neuroinflammation and BBB disruption. LC-MS analysis was used to quantify PBUT
serum concentrations in control (Sham) and IRI mice. Additionally, the mouse brains were
harvested and processed into formalin-fixed paraffin-embedded (FFPE) blocks and sliced for
immunofluorescence experiments. We then validated methods to study microglial activation,
by using different markers (i.e., IBA-1 and P2Y12) as well as computational analysis of
microglial morphology. To assess the structural and functional integrity of the BBB, we stained
for laminin, a crucial component of the vascular basement membrane as well as GFAP and
Aquaporin 4 (AQP4), both astrocytic markers that can give us valuable information about
astroglial reactivity and BBB integrity. Our study lays the groundwork for investigating the
neurological effects of PBUTs in the context of kidney injury.
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