Abstract: TH-OR009
Neuroinflammation and Neurological Dysfunction After AKI Is Driven by Kidney-Released Osteopontin and Not Uremia
Session Information
- AKI Progression and Resolution: Cellular and Molecular Insights
November 06, 2025 | Location: Room 320A, Convention Center
Abstract Time: 05:50 PM - 06:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Weerasinghe Mudiyanselage, Poornima Dilhani Ekanayake, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
- Ning, Liang, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
- Ojha, Rupal, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
- Komaru, Yohei, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
- Kefalogianni, Eirini, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
- Friess, Stuart, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
- Celorrio Navarro, Marta, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
- Herrlich, Andreas, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
Background
Acute kidney injury (AKI) or kidney failure is very common in hospitalized patients. 50% of AKI patients develop persistent neurocognitive dysfunction even after AKI is resolved and 7% of patients develop dementia within 2 years after AKI. Mechanisms driving this kidney-brain crosstalk are largely unknown, but limited studies suggested neuroinflammation may play a role.
Methods
AKI was induced in mice using bilateral ischemia reperfusion injury and were tested for neurocognitive function by using a battery of behavioral tests at different time point. Hippocampal inflammatory changes were assessed using flow cytometry and histological analysis.
Results
Here we show that neurocognitive dysfunction after AKI is not caused by uremia but rather by monocytic inflammation of the hippocampus. Monocytes infiltrated the hippocampus acutely after AKI and accumulated chronically long after AKI resolution. This accurately correlated with reduced exploration in the elevated plus maze test, and chronically with lower recall memory to cue/context in contextual fear conditioning testing. We previously showed that circulating osteopontin (OPN) released by the kidney during AKI causes remote lung inflammation with respiratory failure. OPN global KO mice were protected against AKI-induced remote hippocampal inflammation and neurological dysfunction. Similar to kidney-lung crosstalk, in kidney-brain crosstalk after AKI OPN mRNA and protein were upregulated in the kidney and serum OPN protein was elevated. However, OPN mRNA and protein levels in the hippocampus after AKI were very low overall, suggesting a role for circulating OPN. OPN-KI mice with an OPN point mutation rendering it uncleavable by thrombin were protected acutely and chronically against monocytic neuroinflammation and neurocognitive dysfunction after AKI, showing that OPN requires thrombin cleavage in kidney-brain crosstalk.
Conclusion
Together with our previous findings that linked kidney-released OPN to kidney-lung crosstalk, our kidney-brain data suggest that circulating OPN should also be considered in other secondary organ complications of AKI.
Funding
- NIDDK Support