{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T07:01:05Z","timestamp":1762326065879,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kyungpook National University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Destabilization of heme proteins is recognized to play a role in acute kidney injury (AKI). Hemopexin (Hpx), known for its role in binding heme, mitigates free heme toxicity. Despite this, the potential adverse effects of Hpx deposition in kidney tissues and its impact on kidney function are not fully understood. Deferoxamine (DFO) chelates iron released from heme and mitigates associated kidney damage. Therefore, this study aimed to evaluate whether Hpx contributes to kidney injury in an ischemia-reperfusion injury (IRI) induced AKI model and to investigate if DFO could alleviate this damage. Mice were categorized into five groups: Sham-Vehicle, Sham-Hpx, IRI-Vehicle, IRI-Hpx, and IRI-Hpx-DFO. Decline in kidney function was observed exclusively in the IRI group, independent of Hpx injection. Serum Hpx levels remained comparable across all groups, and administration of Hpx did not alter serum Hpx levels or kidney function after 24 hours. Although increased Hpx deposition in kidneys was noted in both the IRI and Hpx groups, this accumulation did not correlate with impaired kidney function. Additionally, DFO did not exhibit a protective effect against kidney injury. In summary, Hpx does not directly induce kidney injury and cannot be considered a biomarker for kidney damage caused by IRI.<\/jats:p>","DOI":"10.3390\/biom14121522","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T11:26:08Z","timestamp":1732706768000},"page":"1522","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Is Hemopexin a Nephrotoxin or a Marker of Kidney Injury in Renal Ischemia-Reperfusion?"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7318-5753","authenticated-orcid":false,"given":"You Hyun","family":"Jeon","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun-Joo","family":"Oh","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Se-Hyun","family":"Oh","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"Cell and Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5517-9886","authenticated-orcid":false,"given":"Jeong-Hoon","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"Cell and Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hee-Yeon","family":"Jung","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9774-3665","authenticated-orcid":false,"given":"Ji-Young","family":"Choi","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7031-5214","authenticated-orcid":false,"given":"Jang-Hee","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"Cell and Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0953-3343","authenticated-orcid":false,"given":"Sun-Hee","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1344-3455","authenticated-orcid":false,"given":"Yong-Lim","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"Cell and Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4648-0324","authenticated-orcid":false,"given":"Chan-Duck","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"Cell and Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41572-021-00284-z","article-title":"Acute kidney injury","volume":"7","author":"Kellum","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.2215\/CJN.15611219","article-title":"AKI!Now Initiative: Recommendations for Awareness, Recognition, and Management of AKI","volume":"15","author":"Liu","year":"2020","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1681\/ASN.2015010006","article-title":"Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression","volume":"26","author":"Venkatachalam","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1056\/NEJMra1214243","article-title":"Acute kidney injury and chronic kidney disease as interconnected syndromes","volume":"371","author":"Chawla","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"c179","DOI":"10.1159\/000339789","article-title":"KDIGO clinical practice guidelines for acute kidney injury","volume":"120","author":"Khwaja","year":"2012","journal-title":"Nephron Clin. Pract."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1007\/s00134-017-4715-2","article-title":"Ten shortcomings of the current definition of AKI","volume":"43","author":"Schetz","year":"2017","journal-title":"Intensive Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1053\/j.ajkd.2020.05.015","article-title":"Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis","volume":"76","author":"Albert","year":"2020","journal-title":"Am. J. Kidney Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s12967-021-02776-8","article-title":"The value of kidney injury molecule 1 in predicting acute kidney injury in adult patients: A systematic review and Bayesian meta-analysis","volume":"19","author":"Geng","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1007\/s00134-021-06454-7","article-title":"Acute kidney injury in the critically ill: An updated review on pathophysiology and management","volume":"47","author":"Pickkers","year":"2021","journal-title":"Intensive Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1093\/ckj\/sfaa142","article-title":"Acute kidney injury pathology and pathophysiology: A retrospective review","volume":"14","author":"Gaut","year":"2021","journal-title":"Clin. Kidney J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/s41581-019-0181-0","article-title":"Mechanisms of haemolysis-induced kidney injury","volume":"15","author":"Nur","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1124\/pr.55.3.5","article-title":"Different Faces of the Heme-Heme Oxygenase System in Inflammation","volume":"55","author":"Wagener","year":"2003","journal-title":"Pharmacol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.34067\/KID.0005442022","article-title":"Heme Proteins and Kidney Injury: Beyond Rhabdomyolysis","volume":"3","author":"Nath","year":"2022","journal-title":"Kidney360"},{"key":"ref_14","first-page":"457","article-title":"Induction of kidney heme oxygenase-1 (HSP32) mRNA and protein by ischemia\/reperfusion: Possible role of heme as both promotor of tissue damage and regulator of HSP32","volume":"264","author":"Maines","year":"1993","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1038\/ki.1995.414","article-title":"Induction of heme oxygenase in toxic renal injury: A protective role in cisplatin nephrotoxicity in the rat","volume":"48","author":"Agarwal","year":"1995","journal-title":"Kidney Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1146\/annurev-nutr-062320-112625","article-title":"Molecular Mechanisms of Iron and Heme Metabolism","volume":"42","author":"Dutt","year":"2022","journal-title":"Annu. Rev. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1124\/pr.107.07104","article-title":"Pharmacological and clinical aspects of heme oxygenase","volume":"60","author":"Abraham","year":"2008","journal-title":"Pharmacol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"F317","DOI":"10.1152\/ajprenal.00606.2012","article-title":"Age sensitizes the kidney to heme protein-induced acute kidney injury","volume":"304","author":"Nath","year":"2013","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1172\/JCI115847","article-title":"Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat","volume":"90","author":"Nath","year":"1992","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/S0891-5849(96)00499-6","article-title":"The toxicities of native and modified hemoglobins","volume":"22","author":"Everse","year":"1997","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.toxlet.2005.03.004","article-title":"Free heme toxicity and its detoxification systems in human","volume":"157","author":"Kumar","year":"2005","journal-title":"Toxicol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1681\/ASN.2018100979","article-title":"Iron, Hepcidin, and Death in Human AKI","volume":"30","author":"Leaf","year":"2019","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Bellotti, D., and Remelli, M. (2021). Deferoxamine B: A Natural, Excellent and Versatile Metal Chelator. Molecules, 26.","DOI":"10.3390\/molecules26113255"},{"key":"ref_24","first-page":"F438","article-title":"Evidence suggesting a role for hydroxyl radical in glycerol-induced acute renal failure","volume":"255","author":"Shah","year":"1988","journal-title":"Am. J. Physiol."},{"key":"ref_25","first-page":"F539","article-title":"Hemoglobin- and myoglobin-induced acute renal failure in rats: Role of iron in nephrotoxicity","volume":"255","author":"Paller","year":"1988","journal-title":"Am. J. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1089\/104454902753759717","article-title":"Hemopexin: Structure, function, and regulation","volume":"21","author":"Tolosano","year":"2002","journal-title":"DNA Cell Biol."},{"key":"ref_27","first-page":"1044","article-title":"Hemopexin deficiency promotes acute kidney injury in sickle cell disease","volume":"135","author":"Hazra","year":"2020","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1111\/j.1523-1755.2005.00438.x","article-title":"Protease activity of plasma hemopexin","volume":"68","author":"Bakker","year":"2005","journal-title":"Kidney Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1046\/j.1523-1755.2000.00996.x","article-title":"Induction of experimental proteinuria in vivo following infusion of human plasma hemopexin","volume":"57","author":"Cheung","year":"2000","journal-title":"Kidney Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1016\/j.kint.2022.07.024","article-title":"Hemopexin accumulates in kidneys and worsens acute kidney injury by causing hemoglobin deposition and exacerbation of iron toxicity in proximal tubules","volume":"102","author":"Fan","year":"2022","journal-title":"Kidney Int."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Poillerat, V., Gentinetta, T., Leon, J., Wassmer, A., Edler, M., Torset, C., Luo, D., Tuffin, G., and Roumenina, L.T. (2020). Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01684"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e031219","DOI":"10.1161\/JAHA.123.031219","article-title":"Deferasirox Targeting Ferroptosis Synergistically Ameliorates Myocardial Ischemia Reperfusion Injury in Conjunction With Cyclosporine A","volume":"13","author":"Ishimaru","year":"2024","journal-title":"J. Am. Heart Assoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1182\/bloodadvances.2020001698","article-title":"Heme activates platelets and exacerbates rhabdomyolysis-induced acute kidney injury via CLEC-2 and GPVI\/FcR\u03b3","volume":"5","author":"Oishi","year":"2021","journal-title":"Blood Adv."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.kint.2020.09.033","article-title":"Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis","volume":"99","author":"Boudhabhay","year":"2021","journal-title":"Kidney Int."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Smith, A., and McCulloh, R.J. (2015). Hemopexin and haptoglobin: Allies against heme toxicity from hemoglobin not contenders. Front. Physiol., 6.","DOI":"10.3389\/fphys.2015.00187"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1681\/ASN.2006080894","article-title":"Physiology and pathophysiology of heme: Implications for kidney disease","volume":"18","author":"Tracz","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"831596","DOI":"10.1155\/2013\/831596","article-title":"Vasculotoxic and Proinflammatory Effects of Plasma Heme: Cell Signaling and Cytoprotective Responses","volume":"2013","author":"Belcher","year":"2013","journal-title":"ISRN Oxidative Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1016\/S0002-9440(10)65024-9","article-title":"The indispensability of heme oxygenase-1 in protecting against acute heme protein-induced toxicity in vivo","volume":"156","author":"Nath","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1182\/blood-2015-08-663245","article-title":"Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease","volume":"127","author":"Vinchi","year":"2016","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Belcher, J.D., Chen, C., Nguyen, J., Abdulla, F., Zhang, P., Nguyen, H., Nguyen, P., Killeen, T., Miescher, S.M., and Brinkman, N. (2018). Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: Role of heme oxygenase-1 induction. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0196455"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Ashouri, R., Fangman, M., Burris, A., Ezenwa, M.O., Wilkie, D.J., and Dor\u00e9, S. (2021). Critical Role of Hemopexin Mediated Cytoprotection in the Pathophysiology of Sickle Cell Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126408"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1681\/ASN.2007080940","article-title":"Hemopexin induces nephrin-dependent reorganization of the actin cytoskeleton in podocytes","volume":"19","author":"Lennon","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1007\/s00467-005-1936-3","article-title":"Altered activity of plasma hemopexin in patients with minimal change disease in relapse","volume":"20","author":"Bakker","year":"2005","journal-title":"Pediatr. Nephrol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"F1460","DOI":"10.1152\/ajprenal.00426.2012","article-title":"Renal cortical hemopexin accumulation in response to acute kidney injury","volume":"303","author":"Zager","year":"2012","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Fitridge, R., and Thompson, M. (2011). Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists, University of Adelaide Press. Chapter 18.","DOI":"10.1017\/UPO9781922064004"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kalapotharakos, G., Murtoniemi, K., \u00c5kerstr\u00f6m, B., H\u00e4m\u00e4l\u00e4inen, E., Kajantie, E., R\u00e4ikk\u00f6nen, K., Villa, P., Laivuori, H., and Hansson, S.R. (2019). Plasma Heme Scavengers Alpha-1-Microglobulin and Hemopexin as Biomarkers in High-Risk Pregnancies. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00300"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1161\/STROKEAHA.117.018724","article-title":"Carotid Atheroma From Men Has Significantly Higher Levels of Inflammation and Iron Metabolism Enabled by Macrophages","volume":"49","author":"Yuan","year":"2018","journal-title":"Stroke"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13075-019-1846-6","article-title":"Mass spectrometry-based analysis of cerebrospinal fluid from arthritis patients-immune-related candidate proteins affected by TNF blocking treatment","volume":"21","author":"Estelius","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1111\/bjh.15996","article-title":"The effects of hydroxycarbamide on the plasma proteome of children with sickle cell anaemia","volume":"186","author":"Brewin","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_50","first-page":"457","article-title":"Study of urinary markers of different podocytopathies by proteomic analysis","volume":"95","author":"Vinogradov","year":"2023","journal-title":"Ter. Arkh."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Zhou, L., Han, S., Guo, J., Qiu, T., Zhou, J., and Shen, L. (2022). Ferroptosis-A New Dawn in the Treatment of Organ Ischemia-Reperfusion Injury. Cells, 11.","DOI":"10.3390\/cells11223653"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Lechuga, G.C., Napole\u00e3o-P\u00eago, P., Morel, C.M., Provance, D.W., and De-Simone, S.G. (2022). New Insights into Hemopexin-Binding to Hemin and Hemoglobin. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073789"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/12\/1522\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:41:02Z","timestamp":1760114462000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/12\/1522"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,27]]},"references-count":52,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["biom14121522"],"URL":"https:\/\/doi.org\/10.3390\/biom14121522","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2024,11,27]]}}}