{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T15:32:03Z","timestamp":1781796723370,"version":"3.54.5"},"reference-count":39,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wenzhou Science and Technology Bureau Project","award":["Y2023966"],"award-info":[{"award-number":["Y2023966"]}]},{"name":"Zhejiang Provincial Department of Education General Scientific Research Project","award":["Y202560002"],"award-info":[{"award-number":["Y202560002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Renal ischemia\u2013reperfusion injury (IRI) is a major cause of acute kidney injury. Estradiol (E2) and the selective estrogen receptor modulator raloxifene (RAL) reduce organ dysfunction, potentially via heme oxygenase-1 (HO-1)\u2013mediated antioxidant and anti-inflammatory effects. This study examined whether E2 and RAL protect against IRI through G protein-coupled estrogen receptor (GPER)\u2013dependent activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)\/HO-1 pathway in ovariectomized (OVX) mice; OVX IRI mice were pretreated for four weeks with E2, RAL, RAL + ML385 (Nrf2 inhibitor), or RAL + G15 (GPER antagonist). Renal histology, inflammatory and oxidative markers, and nuclear Nrf2 levels were assessed; OVX IRI increased interleukin-1\u03b2 (IL-1\u03b2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-\u03b1), and malondialdehyde (MDA) and decreased superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH); nuclear Nrf2 was low in sham and OVX IRI groups. E2 and RAL improved renal function and histology, reduced inflammation and oxidative stress, restored GPER expression, increased nuclear Nrf2, and upregulated HO-1 and NAD(P)H:quinone oxidoreductase 1 (NQO1). Co-treatment with ML385 or G15 reversed RAL\u2019s benefits, reduced nuclear Nrf2, and worsened injury; E2 and RAL exert renoprotective effects against OVX-related renal IRI in a manner consistent with GPER-dependent Nrf2 nuclear translocation, which suggests involvement of the downstream antioxidant gene activation pathway.<\/jats:p>","DOI":"10.3390\/ijms27073070","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:33:33Z","timestamp":1774622013000},"page":"3070","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Estradiol and Raloxifene Protect Ovariectomized Mice from Acute Kidney Injury via G Protein-Coupled Estrogen Receptor-Mediated Nuclear Factor Erythroid 2-Related Factor 2\/Heme Oxygenase-1 Activation"],"prefix":"10.3390","volume":"27","author":[{"given":"Yichuan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbo","family":"Song","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Wenzhou Medical University, Wenzhou 325015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihua","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maochao","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"F149","DOI":"10.1152\/ajprenal.00099.2020","article-title":"Sex differences in renal ischemia-reperfusion injury","volume":"319","author":"Hosszu","year":"2020","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1007\/s11064-019-02769-6","article-title":"Sex differences in ischemia\/reperfusion injury: The role of mitochondrial permeability transition","volume":"44","author":"Fels","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1080\/0886022X.2021.1901739","article-title":"Estrogen and estrogen receptors in kidney diseases","volume":"43","author":"Ma","year":"2021","journal-title":"Ren. Fail."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Andrianova, N.V., Brezgunova, A.A., Buyan, M.I., Makievskaya, C.I., Buyan, A.I., Cherkesova, K.S., Pevzner, I.B., Zorova, L.D., Zorov, D.B., and Plotnikov, E.Y. (2024). Sex-specific effects of estradiol and progesterone in ischemic kidney injury. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063155"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"122038","DOI":"10.1016\/j.lfs.2023.122038","article-title":"Estrogen-mediated mitigation of cardiac oxidative stress in ovariectomized rats is associated with upregulated cardiac circadian clock Per2 and heart-specific miRNAs","volume":"331","author":"Ahmed","year":"2023","journal-title":"Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"104859","DOI":"10.1016\/j.ebiom.2023.104859","article-title":"Identifying actionable druggable targets for breast cancer: Mendelian randomization and population-based analyses","volume":"98","author":"Zhang","year":"2023","journal-title":"EBioMedicine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1093\/jac\/dkac069","article-title":"Raloxifene prevents intracellular invasion of pathogenic bacteria through modulation of cell metabolic pathways","volume":"77","author":"Chang","year":"2022","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13293-019-0219-9","article-title":"Estrogen receptor profiles across tissues from male and female Rattus norvegicus","volume":"10","author":"Hutson","year":"2019","journal-title":"Biol. Sex Differ."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Notas, G., Kampa, M., and Castanas, E. (2020). G protein-coupled estrogen receptor in immune cells and its role in immune-related diseases. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.579420"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1097\/FJC.0b013e3182135f1c","article-title":"Vasodilation in response to the GPR30 agonist G-1 is not different from estradiol in the mRen2. Lewis female rat","volume":"57","author":"Lindsey","year":"2011","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111065","DOI":"10.1016\/j.cbi.2024.111065","article-title":"G protein-coupled estrogen receptor selective agonist, G1, improves the molecular and biochemical markers in a cisplatin mouse model of CKD","volume":"398","author":"Ahmed","year":"2024","journal-title":"Chem.-Biol. Interact."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1097\/ALN.0b013e3181c98da9","article-title":"Estrogen is renoprotective via a nonreceptor-dependent mechanism after cardiac arrest in vivo","volume":"112","author":"Hutchens","year":"2010","journal-title":"Anesthesiology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1097\/GME.0000000000000864","article-title":"Involvement of HSP70 and HO-1 in the protective effects of raloxifene on multiple organ dysfunction syndrome by endotoxemia in ovariectomized rats","volume":"24","author":"Shen","year":"2017","journal-title":"Menopause"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3705","DOI":"10.1111\/jcmm.13280","article-title":"Activation of autophagy is involved in the protective effect of 17\u03b2-oestradiol on endotoxaemia-induced multiple organ dysfunction in ovariectomized rats","volume":"21","author":"Chung","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ahmadian Elmi, M., Motamed, N., and Picard, D. (2023). Proteomic Analyses of the G Protein-Coupled Estrogen Receptor GPER1 Reveal Constitutive Links to Endoplasmic Reticulum, Glycosylation, Trafficking, and Calcium Signaling. Cells, 12.","DOI":"10.3390\/cells12212571"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e165812","DOI":"10.1172\/JCI165812","article-title":"PJA1 mediates the effects of astrocytic GPR30 on learning and memory in female mice","volume":"133","author":"Wang","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1126\/science.aba9001","article-title":"GPER1 is required to protect fetal health from maternal inflammation","volume":"371","author":"Harding","year":"2021","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1210\/mend.14.10.0532","article-title":"Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF","volume":"14","author":"Filardo","year":"2000","journal-title":"Mol. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1126\/science.1106943","article-title":"A transmembrane intracellular estrogen receptor mediates rapid cell signaling","volume":"307","author":"Revankar","year":"2005","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1210\/en.2004-1064","article-title":"Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells","volume":"146","author":"Thomas","year":"2005","journal-title":"Endocrinology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/nrendo.2011.122","article-title":"The G-protein-coupled estrogen receptor GPER in health and disease","volume":"7","author":"Prossnitz","year":"2011","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1111\/j.1476-5381.2011.01649_1.x","article-title":"Guide to receptors and channels (GRAC)","volume":"164","author":"Alexander","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1021\/acs.molpharmaceut.1c00018","article-title":"Proteolytic targeting chimeras with specificity for plasma membrane and intracellular estrogen receptors","volume":"18","author":"Lu","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"108666","DOI":"10.1016\/j.biopha.2019.108666","article-title":"G protein-coupled estrogen receptor activation improves contractile and diastolic functions in rat renal interlobular artery to protect against renal ischemia reperfusion injury","volume":"112","author":"Chang","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e015110","DOI":"10.1161\/JAHA.119.015110","article-title":"Evidence for G-Protein\u2013Coupled Estrogen Receptor as a Pronatriuretic Factor","volume":"9","author":"Gohar","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17240","DOI":"10.1038\/s41598-020-73974-5","article-title":"A single dose of estrogen during hemorrhagic shock protects against kidney injury whereas estrogen restoration in ovariectomized mice is ineffective","volume":"10","author":"Cuny","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R297","DOI":"10.1152\/ajpregu.00267.2020","article-title":"Activation of G protein-coupled estrogen receptor 1 ameliorates proximal tubular injury and proteinuria in Dahl salt-sensitive female rats","volume":"320","author":"Gohar","year":"2021","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mapuskar, K.A., Pulliam, C.F., Zepeda-Orozco, D., Griffin, B.R., Furqan, M., Spitz, D.R., and Allen, B.G. (2023). Redox regulation of Nrf2 in cisplatin-induced kidney injury. Antioxidants, 12.","DOI":"10.3390\/antiox12091728"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3991","DOI":"10.1111\/bph.15834","article-title":"Leonurine alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signalling pathway","volume":"179","author":"Hu","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_30","first-page":"580","article-title":"The effects of exercise training and high triglyceride diet in an estrogen depleted rat model: The role of the heme oxygenase system and inflammatory processes in cardiovascular risk","volume":"17","author":"Varga","year":"2018","journal-title":"J. Sports Sci. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1097\/TP.0000000000004194","article-title":"The Selective Estrogen Receptor Modulator, Raloxifene, Is Protective Against Renal Ischemia\u2013Reperfusion Injury","volume":"106","author":"Hernandez","year":"2022","journal-title":"Transplantation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1038\/s41419-020-03159-5","article-title":"Raloxifene prevents stress granule dissolution, impairs translational control and promotes cell death during hypoxia in glioblastoma cells","volume":"11","author":"Attwood","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s13402-020-00559-9","article-title":"Raloxifene inhibits pancreatic adenocarcinoma growth by interfering with ER\u03b2 and IL-6\/gp130\/STAT3 signaling","volume":"44","author":"Pozios","year":"2021","journal-title":"Cell. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s12032-022-01909-3","article-title":"Raloxifene potentiates the effect of gefitinib in triple-negative breast cancer cell lines","volume":"40","author":"Taurin","year":"2022","journal-title":"Med. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.21873\/invivo.13190","article-title":"The combination sorafenib-raloxifene-loratadine as a novel potential therapeutic approach against human liver cancer","volume":"37","author":"Camacho","year":"2023","journal-title":"In Vivo"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1080\/15548627.2023.2218764","article-title":"GPX4 in cell death, autophagy, and disease","volume":"19","author":"Xie","year":"2023","journal-title":"Autophagy"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.maturitas.2013.06.003","article-title":"Tissue-selective estrogen complexes for postmenopausal women","volume":"76","author":"Mirkin","year":"2013","journal-title":"Maturitas"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.maturitas.2016.01.015","article-title":"Modeling menopause: The utility of rodents in translational behavioral endocrinology research","volume":"87","author":"Koebele","year":"2016","journal-title":"Maturitas"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"F1098","DOI":"10.1152\/ajprenal.00199.2018","article-title":"Rodent models of AKI-CKD transition","volume":"315","author":"Fu","year":"2018","journal-title":"Am. J. Physiol.-Ren. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/3070\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:34:58Z","timestamp":1774622098000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/3070"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":39,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27073070"],"URL":"https:\/\/doi.org\/10.3390\/ijms27073070","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]}}}