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Abstract Details

Circulating Osteopontin Released by the Injured Kidney Drives Hippocampal Neuroinflammation and Neurologic Dysfunction in Acute Kidney Injury Independent of Uremia
General Neurology
P8 - Poster Session 8 (11:45 AM-12:45 PM)
7-009

In this study we aimed to find the specific factors and mechanisms that causes neurologic impairment in acute kidney injury (AKI).
AKI is a common clinical problem with high mortality and morbidity from secondary organ complications, including acute neurologic dysfunction, such as delirium. Delirium prolongs hospital stay and often leads to long-term cognitive decline, driving significant individual, healthcare and societal cost. Specific causes and mechanisms that drive this kidney-brain crosstalk are still unresolved but thought to include uremic toxin-induced neuroinflammation enhanced by increased blood brain barrier (BBB) permeability. 

AKI was induced in mice using bilateral ischemia reperfusion injury. At 48 hours after AKI mice were tested for neurologic function and inflammatory changes with elevated plus maze test and flow cytometry and histological analysis respectively. 

Here we show in mice that a specific alarmin, circulating osteopontin (OPN, Spp1), released from the injured kidney causes acute hippocampal monocytic neuroinflammation and neurologic dysfunction independent of uremia or increased BBB permeability. OPN was upregulated in the injured kidney and circulation after AKI, but not in the brain and systemic application of an OPN neutralizing antibody was protective. AKI-induced thrombin cleavage of osteopontin was required to induce monocyte chemoattractant chemokine ligand 2 (CCL2) expression in the hippocampus, and a CCL2 neutralizing antibody prevented hippocampal neuroinflammation and neurologic dysfunction. Mice lacking OPN (OPN-KO) or unable to activate OPN by thrombin cleavage (OPN-KI) showed kidney injury and uremia like WT animals but were both protected. 

Our results suggest that a specific circulating alarmin-type molecule, OPN, drives neuroinflammation and neurologic dysfunction after AKI, rather than reduced excretion of uremic retention solutes or changes of the blood brain barrier.
Authors/Disclosures
Poornima D. Ekanayake WM, PhD
PRESENTER 		Dr. Ekanayake WM has nothing to disclose.
LIANG NING, MD, PhD Mr. NING has nothing to disclose.
Marta Celorrio Miss Celorrio has nothing to disclose.
STUART FRIESS, MD Dr. FRIESS has nothing to disclose.
Andreas Herrlich, MD, PhD Prof. Herrlich has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wiley. The institution of Prof. Herrlich has received research support from NIH.