{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:12:23Z","timestamp":1768450343591,"version":"3.49.0"},"reference-count":54,"publisher":"Portland Press Ltd.","issue":"22","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":26,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82300771"],"award-info":[{"award-number":["82300771"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2023M730678"],"award-info":[{"award-number":["2023M730678"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,27]]},"abstract":"<jats:p>Acute kidney injury (AKI) is recognized as a critical clinical problem, and pharmacological therapeutic options for AKI remain limited. Our previous study confirmed that Rac GTPase-activating protein 1 (RacGAP1) effectively promoted the repair of tubular epithelial cells in vitro. Further investigation is needed to determine whether boosting the expression of RacGAP1 in vivo helps protect against AKI. Herein, lipid-coated calcium phosphate (LCP) nanoparticles loaded with RacGAP1 plasmids (pRacGAP1-LCP) were generated and subsequently characterized based on their size, zeta potential, and morphological features. Animal models of AKI induced by ischemia\/reperfusion (I\/R) injury (IRI) were established in C57BL\/6 mice, and pRacGAP1-LCP was injected into the tail vein to explore the role of RacGAP1 on renal IRI in vivo. The therapeutic efficacy of pRacGAP1-LCP against IRI was assessed through western blotting, real-time PCR, and histological analyses. The effects of RacGAP1 on mitochondrial homeostasis were further examined in mouse renal tubular epithelial cells (mRTECs). Serial administrations of pRacGAP1-LCP led to a significant increase in RacGAP1 expression in murine kidneys. This therapeutic intervention effectively attenuated AKI, as evidenced by down-regulation of AKI biomarkers, amelioration of renal histopathological damage, and suppression of both apoptosis and inflammatory responses. Characteristic mitochondrial abnormalities, diminished ATP production, and excessive lipid droplet accumulation were observed in tubular cells of IRI mice. Notably, pRacGAP1-LCP treatment reversed these pathological alterations and up-regulated the expression of PGC-1\u03b1 and CPT-1\u03b1, indicating that RacGAP1 exerted its reno-protective effects through enhanced mitochondrial biogenesis and fatty acid oxidation (FAO). To further investigate the role of RacGAP1 in mitochondrial homeostasis, we employed an ATP depletion-repletion (ATP D-R) model in mRTECs. Crucially, RacGAP1 effectively restored ATP production, mtDNA copy number, and oxygen consumption rate (OCR) in mRTECs after ATP D-R treatment. RacGAP1 overexpression also suppressed mitochondrial depolarization, fragmentation, and reactive oxygen species (ROS) generation. Conversely, RacGAP1 knockdown exacerbated mitochondrial defects in mRTECs exposed to ATP D-R. In summary, this study uncovers that RacGAP1 overexpression protects against renal injury and mitochondrial dysfunction, highlighting its therapeutic promise for AKI. The LCP nanoparticle exhibits potential as a precise and efficient delivery platform and presents a viable option for AKI therapy.<\/jats:p>","DOI":"10.1042\/cs20256110","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T12:44:06Z","timestamp":1763037846000},"page":"1571-1590","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nanoparticle-mediated overexpression of RacGAP1 protects against renal ischemia\/reperfusion injury by maintaining mitochondrial homeostasis"],"prefix":"10.1042","volume":"139","author":[{"given":"Weiran","family":"Zhou","sequence":"first","affiliation":[{"name":"1Divisionof Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China"},{"name":"2Shanghai Key Laboratory of Kidney Diseases and Blood Purification, Shanghai, China"},{"name":"3Shanghai Institute of Kidney and Dialysis, Shanghai, China"},{"name":"4Shanghai Medical Center of Kidney, Shanghai, 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