Acute Kidney Injury Induces Neurological Impairment Through Early Blood-Brain Barrier Disruption and Endothelial Transcytosis in Mice
Mickaël Bobot, Sandrine Placier, Chloé Samson, Aurélie Prignon, Liliane Louedec, Perrine Frère, Marie-Christine Verpont, Franck Lebrin, Samantha Fernandez, Mustapha Naamoun, Nathalie McKay, Guillaume Hache, Benjamin Guillet, Vincent Nail, Lauriane Mascaro, Edwige Tellier, Stéphane Burtey, Juliette Hadchouel, Pierre GalichonObjectives:
Acute kidney injury (AKI) is associated with central neurologic complications, notably in critical care, the mechanisms of which are poorly understood. Blood-brain barrier (BBB) disruption is a central mechanism associated with cognitive impairment in chronic kidney disease. The objectives of this study were to characterize the influence of AKI on brain alteration and BBB permeability in a preclinical model.
Design:
We performed a mouse model of unilateral renal ischemia-reperfusion injury without or with AKI (obtained by removing the contralateral kidney before ischemia).
Subjects:
All animals were 7-week-old male C57Bl/6J mice, randomly assigned to groups: AKI, kidney ischemia-reperfusion alone, or control.
Interventions:
We assessed neurologic impairment using the modified neurologic severity score and motricity evaluations, quantified BBB disruption by cerebral extravasation of Evans blue and positron emission tomography (PET)/CT imaging with Gallium-68 diethylenetriaminepentaacetic acid ( 68 Ga-DTPA), and performed immunohistochemistry and electron microscopy on brain sections.
Measurements and Main Results:
In mice with AKI, we found neurologic impairment, decreased spontaneous motricity, and cerebral extravasation of Evans blue, which were not observed in mice with renal ischemia-reperfusion without nephrectomy. Cerebral 68 Ga-DTPA PET/CT imaging with imaging confirmed the BBB disruption. In addition, we observed more extracellular vesicles in cerebral endothelial cells by electron microscopy in AKI mice compared with controls.
Conclusions:
AKI-induced neurologic complications are associated with an early increase in BBB permeability and transcytosis of extracellular vesicles in cerebral endothelium.