Midkine‐Mediated Microglia Activation after Renal Injury Promotes Cognitive Impairment Following Ischemic Renal Injury

The mechanism of secondary cognitive impairment following AKI. When renal ischemic injury progresses to fibrosis, renal fibroblasts and damaged tubular cells secrete MDK, which circulates through the bloodstream, crosses the damaged BBB, and accumulates in the hippocampus tissue (an area crucial for learning and memory). The Morris water maze test is used to evaluate the cognitive function of mice subjected to post‐ischemic renal injury, and the results show that AKI mice exhibits cognitive dysfunction, which may be the result of renal fibrosis and its impact on brain function. In hippocampal tissue, MDK is internalized into microglia through the Lrp1 receptor, triggering an inflammatory response in microglia, releasing inflammatory factors, activating the expression of P2ry12, and activating its phagocytic function. The functional changes of microglia mentioned above are considered as a factor leading to cognitive dysfunction. Overall, this study emphasizes the complex interplay between kidney health and cognitive function, indicating that AKI may have profound impacts beyond the kidneys, affecting brain health and cognitive abilities. Abstract Acute kidney injury (AKI) is associated with a high prevalence of cognitive impairment, the underlying mechanisms remain elusive. This study explores the role of midkine (MDK), upregulated in renal injury, in mediating cognitive dysfunction following post‐ischemic renal injury. Using a mouse model of unilateral renal ischemia‐reperfusion injury, cognitive deficits and blood‐brain barrier disruption is observed. Single‐cell RNA sequencing and ligand‐receptor interaction analysis reveals a strengthened MDK‐LRP1 axis in both the kidneys and hippocampus of mice subjected to ischemic renal injury. MDK, mainly from injured renal tubular cells and fibroblasts, is enriched in peripheral blood and the hippocampus, correlating with increased activation of hippocampal microglia and upregulation of c. It is demonstrated that MDK internalization into microglia via LRP1 upregulated P2ry12 expression, promoting microglial activation and phagocytosis. Inhibiting renal MDK expression with shRNA adenovirus ameliorated cognitive dysfunction and attenuated microglial activation after ischemic renal injury. These findings suggest the MDK‐LRP1 pathway is a key mediator of cognitive dysfunction following ischemic renal injury and a potential therapeutic target for mitigating cognitive decline in AKI patients. It provides a mechanistic link between renal injury, neuroinflammation, and cognitive deficits, highlighting the potential of targeting MDK‐LRP1 signaling to address cognitive impairment after ischemic renal injury. The mechanism of secondary cognitive impairment following AKI. When renal ischemic injury progresses to fibrosis, renal fibroblasts and damaged tubular cells secrete MDK, which circulates through the bloodstream, crosses the damaged BBB, and accumulates in the hippocampus tissue (an area crucial for learning and memory). The Morris water maze test is used to evaluate the cognitive function of mice subjected to post-ischemic renal injury, and the results show that AKI mice exhibits cognitive dysfunction, which may be the result of renal fibrosis and its impact on brain function. In hippocampal tissue, MDK is internalized into microglia through the Lrp1 receptor, triggering an inflammatory response in microglia, releasing inflammatory factors, activating the expression of P2ry12, and activating its phagocytic function. The functional changes of microglia mentioned above are considered as a factor leading to cognitive dysfunction. Overall, this study emphasizes the complex interplay between kidney health and cognitive function, indicating that AKI may have profound impacts beyond the kidneys, affecting brain health and cognitive abilities. Abstract Acute kidney injury (AKI) is associated with a high prevalence of cognitive impairment, the underlying mechanisms remain elusive. This study explores the role of midkine (MDK), upregulated in renal injury, in mediating cognitive dysfunction following post-ischemic renal injury. Using a mouse model of unilateral renal ischemia-reperfusion injury, cognitive deficits and blood-brain barrier disruption is observed. Single-cell RNA sequencing and ligand-receptor interaction analysis reveals a strengthened MDK-LRP1 axis in both the kidneys and hippocampus of mice subjected to ischemic renal injury. MDK, mainly from injured renal tubular cells and fibroblasts, is enriched in peripheral blood and the hippocampus, correlating with increased activation of hippocampal microglia and upregulation of c. It is demonstrated that MDK internalization into microglia via LRP1 upregulated P2ry12 expression, promoting microglial activation and phagocytosis. Inhibiting renal MDK expression with shRNA adenovirus ameliorated cognitive dysfunction and attenuated microglial activation after ischemic renal injury. These findings suggest the MDK-LRP1 pathway is a key mediator of cognitive dysfunction following ischemic renal injury and a potential therapeutic target for mitigating cognitive decline in AKI patients. It provides a mechanistic link between renal injury, neuroinflammation, and cognitive deficits, highlighting the potential of targeting MDK-LRP1 signaling to address cognitive impairment after ischemic renal injury. Advanced Science, EarlyView.