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This study explores the role of midkine (MDK), upregulated in renal injury, in mediating cognitive dysfunction following post\u2010ischemic renal injury. Using a mouse model of unilateral renal ischemia\u2010reperfusion injury, cognitive deficits and blood\u2010brain barrier disruption is observed. Single\u2010cell RNA sequencing and ligand\u2010receptor interaction analysis reveals a strengthened MDK\u2010LRP1 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\u2010LRP1 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\u2010LRP1 signaling to address cognitive impairment after ischemic renal injury.<\/jats:p>","DOI":"10.1002\/advs.202507832","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T05:00:54Z","timestamp":1763960454000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Midkine\u2010Mediated Microglia Activation after Renal Injury Promotes Cognitive Impairment Following Ischemic Renal Injury"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8127-5473","authenticated-orcid":false,"given":"Li","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Andrology Nanjing Drum Tower Hospital the Affiliated hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"},{"name":"Department of Urology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bixiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Andrology Nanjing Drum Tower Hospital the Affiliated hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Andrology Nanjing Drum Tower Hospital the Affiliated hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Andrology Nanjing Drum Tower Hospital the Affiliated hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanyuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Andrology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University of Chinese Medicine  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Andrology Nanjing Drum Tower Hospital the Affiliated hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Andrology Nanjing Drum Tower Hospital the Affiliated hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Andrology Nanjing Drum Tower Hospital the Affiliated hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongqian","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Urology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liuhua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Andrology Nanjing Drum Tower Hospital the Affiliated hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaozhi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Andrology Nanjing Drum Tower Hospital the Affiliated hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"},{"name":"Department of Urology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School  Nanjing Jiangsu 210008 China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,23]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2023.03.025"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30045-3"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2015.11.019"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-020-0266-9"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-57004-7"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-023-00775-0"},{"key":"e_1_2_9_7_1","first-page":"328","volume":"52","author":"Kelly D. 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