{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T23:00:43Z","timestamp":1788476443731,"version":"build-2803163510"},"reference-count":36,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T00:00:00Z","timestamp":1576713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1E1A2A02023467"],"award-info":[{"award-number":["NRF-2017R1E1A2A02023467"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1C1B5076755"],"award-info":[{"award-number":["NRF-2017R1C1B5076755"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1D1A1B03035278"],"award-info":[{"award-number":["NRF-2017R1D1A1B03035278"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Melatonin, a pineal hormone, is well known to regulate the sleep\u2013wake cycle. Besides, the hormone has been shown to display pleiotropic effects arising from its powerful anti-oxidant and anti-inflammatory activities. Recent studies have reported that melatonin exerts protective effects in animal models of kidney disease. However, the potential effects of melatonin on aristolochic acid (AA)-induced nephropathy (AAN) have not yet been investigated. Here, we found that the administration of melatonin ameliorated AA-induced renal dysfunction, as evidenced by decreased plasma levels of blood urea nitrogen and creatinine and histopathological abnormalities such as tubular dilatation and cast formation. The upregulation of tubular injury markers after AA injection was reversed by melatonin. Melatonin also suppressed AA-induced oxidative stress, as evidenced by the downregulation of 4-hydroxynonenal and reduced level of malondialdehyde, and modulated expression of pro-oxidant and antioxidant enzymes. In addition, p53-dependent apoptosis of tubular epithelial cells, infiltration of macrophages and CD4+ T cells into damaged kidneys, and renal expression of cytokines and chemokines were inhibited by melatonin. Moreover, melatonin attenuated AA-induced tubulointerstitial fibrosis through suppression of the tumor growth factor-\u03b2\/Smad signaling pathway. These results suggest that melatonin might be a potential therapeutic agent for AAN.<\/jats:p>","DOI":"10.3390\/biom10010011","type":"journal-article","created":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T03:15:01Z","timestamp":1577070901000},"page":"11","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Protective Effects of Melatonin Against Aristolochic Acid-Induced Nephropathy in Mice"],"prefix":"10.3390","volume":"10","author":[{"given":"Jung-Yeon","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2329-4374","authenticated-orcid":false,"given":"Jaechan","family":"Leem","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8858-5343","authenticated-orcid":false,"given":"Eon Ju","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jadot, I., Decl\u00e8ves, A.E., Nortier, J., and Caron, N. (2017). An Integrated View of Aristolochic Acid Nephropathy: Update of the Literature. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020297"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/ki.2008.129","article-title":"Aristolochic acid nephropathy: A worldwide problem","volume":"74","author":"Debelle","year":"2008","journal-title":"Kidney Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1152\/physiol.00011.2014","article-title":"Melatonin: Exceeding expectations","volume":"29","author":"Reiter","year":"2014","journal-title":"Physiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12525","DOI":"10.1111\/jpi.12525","article-title":"Melatonin and inflammation-Story of a double-edged blade","volume":"65","author":"Hardeland","year":"2018","journal-title":"J. Pineal Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1111\/j.1442-2042.2007.01806.x","article-title":"Protective effects of melatonin on renal failure in pinealectomized rats","volume":"14","author":"Parlakpinar","year":"2007","journal-title":"Int. J. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kim, J.W., Jo, J., Kim, J.Y., Choe, M., Leem, J., and Park, J.H. (2019). Melatonin Attenuates Cisplatin-Induced Acute Kidney Injury through Dual Suppression of Apoptosis and Necroptosis. Biology, 8.","DOI":"10.3390\/biology8030064"},{"key":"ref_7","first-page":"1694","article-title":"Melatonin promoted renal regeneration in folic acid-induced acute kidney injury via inhibiting nucleocytoplasmic translocation of HMGB1 in tubular epithelial cells","volume":"9","author":"Zhu","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20181614","DOI":"10.1042\/BSR20181614","article-title":"Melatonin attenuates acute kidney ischemia\/reperfusion injury in diabetic rats by activation of the SIRT1\/Nrf2\/HO-1 signaling pathway","volume":"39","author":"Shi","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/cbf.1676","article-title":"Melatonin attenuates methotrexate-induced oxidative stress and renal damage in rats","volume":"28","author":"Abraham","year":"2010","journal-title":"Cell Biochem. Funct."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/j.1600-079X.2007.00459.x","article-title":"Melatonin protects from ischemia\/reperfusion-induced renal injury in rats: This effect is not mediated by proinflammatory cytokines","volume":"43","author":"Kurcer","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1081\/JDI-120015677","article-title":"Effects of melatonin administration to rats with glycerol-induced acute renal failure","volume":"24","author":"Ferraz","year":"2002","journal-title":"Ren. Fail."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1111\/j.1600-079X.2004.00113.x","article-title":"Melatonin ameliorates chronic renal failure-induced oxidative organ damage in rats","volume":"36","author":"Sener","year":"2004","journal-title":"J. Pineal Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s10157-017-1505-7","article-title":"Melatonin ameliorates intrarenal renin-angiotensin system in a 5\/6 nephrectomy rat model","volume":"22","author":"Ishigaki","year":"2018","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/jpi.12296","article-title":"Melatonin nephroprotective action in Zucker diabetic fatty rats involves its inhibitory effect on NADPH oxidase","volume":"60","author":"Winiarska","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_15","first-page":"1318","article-title":"Melatonin attenuates renal fibrosis in diabetic mice by activating the AMPK\/PGC1\u03b1 signaling pathway and rescuing mitochondrial function","volume":"19","author":"Li","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.freeradbiomed.2019.04.033","article-title":"Bardoxolone ameliorates TGF-\u03b21-associated renal fibrosis through Nrf2\/Smad7 elevation","volume":"138","author":"Song","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1111\/j.1600-079X.2006.00401.x","article-title":"Melatonin reduces mortality and oxidatively mediated hepatic and renal damage due to diquat treatment","volume":"42","author":"Xu","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kim, J.Y., Jo, J., Kim, K., An, H.J., Gwon, M.K., Gu, H., Kim, H.J., Yang, A.Y., Kim, S.W., and Jeon, E.J. (2019). Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice. Antioxidants, 8.","DOI":"10.3390\/antiox8080322"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1113\/EP085333","article-title":"Protective effect of nitric oxide in aristolochic acid-induced toxic acute kidney injury: An old friend with new assets","volume":"101","author":"Jadot","year":"2016","journal-title":"Exp. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6571676","DOI":"10.1155\/2018\/6571676","article-title":"Pharmacological Inhibition of Caspase-1 Ameliorates Cisplatin-Induced Nephrotoxicity through Suppression of Apoptosis, Oxidative Stress, and Inflammation in Mice","volume":"2018","author":"Kim","year":"2018","journal-title":"Mediat. Inflamm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/ki.2014.65","article-title":"Inhibition of cytochrome P450 2E1 and activation of transcription factor Nrf2 are renoprotective in myoglobinuric acute kidney injury","volume":"86","author":"Wang","year":"2014","journal-title":"Kidney Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/S0272-6386(12)80178-8","article-title":"Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs","volume":"24","author":"Depierreux","year":"1994","journal-title":"Am. J. Kidney Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13086","DOI":"10.1038\/s41598-017-13486-x","article-title":"The proteasome inhibitor bortezomib attenuates renal fibrosis in mice via the suppression of TGF-\u03b21","volume":"7","author":"Zeniya","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1093\/carcin\/bgm082","article-title":"Aristolochic acid mutagenesis: Molecular clues to the aetiology of Balkan endemic nephropathy-associated urothelial cancer","volume":"28","author":"Arlt","year":"2007","journal-title":"Carcinogenesis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.tiv.2011.01.016","article-title":"Aristolochic acid I induced oxidative DNA damage associated with glutathione depletion and ERK1\/2 activation in human cells","volume":"25","author":"Yu","year":"2011","journal-title":"Toxicol. In Vitro"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6086","DOI":"10.3892\/mmr.2015.4167","article-title":"Vitamin C attenuates the toxic effect of aristolochic acid on renal tubular cells via decreasing oxidative stress-mediated cell death pathways","volume":"12","author":"Wu","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/sj.ki.5002714","article-title":"Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation","volume":"73","author":"Pozdzik","year":"2008","journal-title":"Kidney Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.bbrc.2012.06.049","article-title":"Aristolochic acid-induced accumulation of methylglyoxal and N\u03b5-(carboxymethyl)lysine: An important and novel pathway in the pathogenic mechanism for aristolochic acid nephropathy","volume":"423","author":"Li","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1681\/ASN.2008111133","article-title":"Activation of p53 promotes renal injury in acute aristolochic acid nephropathy","volume":"21","author":"Zhou","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1093\/ndt\/gfn140","article-title":"Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy","volume":"23","author":"Pozdzik","year":"2008","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12169","DOI":"10.1038\/s41598-018-30628-x","article-title":"Aristolochic acid I determine the phenotype and activation of macrophages in acute and chronic kidney disease","volume":"8","author":"Honarpisheh","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Isaka, Y. (2018). Targeting TGF-\u03b2 signaling in kidney fibrosis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092532"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/978-981-13-8871-2_16","article-title":"TGF-\u03b2\/Smad and Renal Fibrosis","volume":"1165","author":"Ma","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1177\/147323000303100107","article-title":"The beneficial effect of melatonin on chronic cyclosporin A nephrotoxicity in rats","volume":"31","author":"Sahna","year":"2003","journal-title":"J. Int. Med. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/cbf.1166","article-title":"Reduction of carbon tetrachloride-induced nephropathy by melatonin administration","volume":"23","author":"Ogeturk","year":"2005","journal-title":"Cell Biochem. Funct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1089\/end.2009.0035","article-title":"Melatonin attenuates unilateral ureteral obstruction-induced renal injury by reducing oxidative stress, iNOS, MAPK, and NF-kB expression","volume":"23","author":"Ozbek","year":"2009","journal-title":"J. Endourol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/1\/11\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:43:55Z","timestamp":1760190235000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/1\/11"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,19]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["biom10010011"],"URL":"https:\/\/doi.org\/10.3390\/biom10010011","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,19]]}}}