Circulating Osteopontin (OPN) Released by Kidney Injury Causes Acute and Chronic Hippocampal Neuroinflammation and Behavioral Dysfunction

Background: Acute kidney injury (AKI) is very common in hospitalized patients. 50% of AKI patients show persistent neurocognitive dysfunction long after AKI is resolved and 7% of patients develop dementia within 2 years after AKI. While the pathophysiological mechanism(s) of this kidney-brain crosstalk is largely unknown, limited studies have implicated neuroinflammation as a possible cause. Methods: AKI was induced in WT and OPN-KI mice using bilateral ischemia reperfusion injury. At different survival points after AKI mice were tested for neurocognitive function by using a battery of behavioral tests. Hippocampal inflammatory changes were assessed using flow cytometry and histological analysis. Results: Here we show that monocytes infiltrate the hippocampus acutely and accumulate chronically long after AKI resolution in parallel with neurocognitive dysfunction. Acutely after AKI in wt mice we observed reduced exploration in the elevated plus maze test, and chronically at 1 + 6 months after AKI we observed lower recall memory to cue/context and reduced spatial learning, linking hippocampal neuroinflammation to neurocognitive dysfunction. AKI induced acute and chronic elevations of kidney and serum levels of the innate immune system activating molecule osteopontin (OPN). Although we were able to detect a small trend to increased OPN protein levels in the hippocampus after AKI, hippocampal OPN mRNA expression was not significantly elevated, suggesting either deposition from the circulation or production by infiltrating monocytes. OPN acts via its thrombin cleavage products. OPN-KI mice with an OPN mutation rendering it uncleavable by thrombin were protected acutely and chronically against monocytic neuroinflammation and neurocognitive dysfunction after AKI. OPN injection into OPN-KO mice with AKI induced hippocampal monocyte accumulation and neurocognitive dysfunction, linking circulating osteopontin released from the injured kidney to neurocognitive dysfunction after AKI. Conclusion: Together with our previous findings that linked kidney-released OPN to kidney-lung crosstalk, our kidney-brain data highlight the involvement of this kidney-released soluble mediator in driving secondary brain complications after AKI. Funding: NIDDK Support, Veterans Affairs Support