{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T21:35:48Z","timestamp":1775338548750,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,27]],"date-time":"2022-03-27T00:00:00Z","timestamp":1648339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81503133"],"award-info":[{"award-number":["81503133"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aristolochic acid I (AA I) is one of the most abundant and toxic aristolochic acids that is reported to cause Aristolochic acid nephropathy (AAN). This paper was designed to assess whether mitochondrial Uncoupling Protein 2 (UCP2), which plays an antioxidative and antiapoptotic role, could protect human renal proximal tubular epithelial (HK-2) cells from toxicity induced by AA I. In this study, HK-2 cells were treated with different concentrations of AA I with or without UCP2 inhibitor (genipin). To upregulate the expression of UCP2 in HK-2 cells, UCP2-DNA transfection was performed. The cell viability was evaluated by colorimetric method using MTT. A series of related biological events such as Reactive Oxygen Species (ROS), Glutathione peroxidase (GSH-Px), and Malondialdehyde (MDA) were evaluated. The results showed that the cytotoxicity of AA I with genipin group was much higher than that of AA I alone. Genipin dramatically boosted oxidative stress and exacerbated AA I-induced apoptosis. Furthermore, the increased expression of UCP2 can reduce the toxicity of AA I on HK-2 cells and upregulation of UCP2 expression can reduce AA I-induced oxidative stress and apoptosis. In conclusion, UCP2 might be a potential target for alleviating AA I-induced nephrotoxicity.<\/jats:p>","DOI":"10.3390\/ijms23073674","type":"journal-article","created":{"date-parts":[[2022,3,27]],"date-time":"2022-03-27T21:27:51Z","timestamp":1648416471000},"page":"3674","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Protective Effects of Mitochondrial Uncoupling Protein 2 against Aristolochic Acid I-Induced Toxicity in HK-2 Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Chen","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Etienne Empweb","family":"Anger","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengdi","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenlin","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuxin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2931-798X","authenticated-orcid":false,"given":"Ji","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1111\/j.1523-1755.2005.00277.x","article-title":"Structure activity relationships of aristolochic acid analogues: Toxicity in cultured renal epithelial cells","volume":"67","author":"Balachandran","year":"2005","journal-title":"Kidney Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"569325","DOI":"10.1155\/2014\/569325","article-title":"Chinese Herbs Containing Aristolochic Acid Associated with Renal Failure and Urothelial Carcinoma: A Review from Epidemiologic Observations to Causal Inference","volume":"2014","author":"Yang","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.tox.2019.03.013","article-title":"Comparison of Aristolochic acid I derived DNA adduct levels in human renal toxicity models","volume":"420","author":"Bastek","year":"2019","journal-title":"Toxicology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1097\/MOU.0000000000000806","article-title":"Aristolochic acid and its effect on different cancers in uro-oncology","volume":"30","author":"Rebhan","year":"2020","journal-title":"Curr. Opin. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1016\/j.fct.2007.11.015","article-title":"Short-term toxicity of aristolochic acid, aristolochic acid-I and aristolochic acid-II in rats","volume":"46","author":"Yeh","year":"2008","journal-title":"Food Chem. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1177\/0960327119897099","article-title":"Mitochondrial dysfunction is involved in aristolochic acid I-induced apoptosis in renal proximal tubular epithelial cells","volume":"39","author":"Liu","year":"2020","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.mrfmmm.2006.08.004","article-title":"DNA adduct formation and mutation induction by aristolochic acid in rat kidney and liver","volume":"602","author":"Mei","year":"2006","journal-title":"Mutat. Res.-Fundam. Mol. Mech. Mutagenesis"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Stiborova, M., Arlt, V.M., and Schmeiser, H.H. (2017). DNA Adducts Formed by Aristolochic Acid Are Unique Biomarkers of Exposure and Explain the Initiation Phase of Upper Urothelial Cancer. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102144"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1002\/em.22321","article-title":"Bioactivation mechanisms of N-hydroxyaristolactams: Nitroreduction metabolites of aristolochic acids","volume":"60","author":"Okuno","year":"2019","journal-title":"Environ. Mol. Mutagenesis"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/0140-6736(93)92984-2","article-title":"Rapidly progressive interstitial renal fibrosis in young women: Association with slimming regimen including Chinese herbs","volume":"341","author":"Vanherweghem","year":"1993","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1056\/NEJM200006083422301","article-title":"Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)","volume":"342","author":"Nortier","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s40264-014-0244-x","article-title":"Aristolochic acid nephropathy: Epidemiology, clinical presentation, and treatment","volume":"38","author":"Luciano","year":"2015","journal-title":"Drug. Saf."},{"key":"ref_13","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_14","doi-asserted-by":"crossref","unstructured":"EFSA Panel on Contaminants in the Food Chain (CONTAM), Knutsen, H.K., Alexander, J., Barregard, L., Bignami, M., Bruschweiler, B., Ceccatelli, S., Cottrill, B., Dinovi, M., and Edler, L. (2017). Risks for human health related to the presence of pyrrolizidine alkaloids in honey, tea, herbal infusions and food supplements. EFSA J., 15, e04908.","DOI":"10.2903\/j.efsa.2017.4908"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.toxicon.2019.10.241","article-title":"Health risk associated with the oral consumption of \u201cChiniy-tref\u201d, a traditional medicinal preparation used in Martinique (French West Indies): Qualitative and quantitative analyses of aristolochic acids contained therein","volume":"172","author":"Wattez","year":"2019","journal-title":"Toxicon"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Anger, E.E., Yu, F., and Li, J. (2020). Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031157"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.apsb.2019.03.003","article-title":"Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPK\u03b1\/UCP2 pathway","volume":"9","author":"Hu","year":"2019","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.redox.2018.09.022","article-title":"AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas\/PKA\/CREB\/UCP-2 pathway after subarachnoid hemorrhage in rats","volume":"20","author":"Mo","year":"2019","journal-title":"Redox Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.intimp.2019.03.043","article-title":"UCP2 ameliorates mitochondrial dysfunction, inflammation, and oxidative stress in lipopolysaccharide-induced acute kidney injury","volume":"71","author":"Ding","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1002\/path.5198","article-title":"UCP2-dependent improvement of mitochondrial dynamics protects against acute kidney injury","volume":"247","author":"Qin","year":"2019","journal-title":"J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"F926","DOI":"10.1152\/ajprenal.00118.2017","article-title":"UCP2 attenuates apoptosis of tubular epithelialcells in renal ischemia-reperfusion injury","volume":"313","author":"Zhou","year":"2017","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"108914","DOI":"10.1016\/j.biopha.2019.108914","article-title":"UCP2 alleviates tubular epithelial cell apoptosis in lipopolysaccharide-induced acute kidney injury by decreasing ROS production","volume":"115","author":"Zhong","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1093\/mutage\/17.4.265","article-title":"Aristolochic acid as a probable human cancer hazard in herbal remedies: A review","volume":"17","author":"Arlt","year":"2002","journal-title":"Mutagenesis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.etp.2016.03.003","article-title":"Oral exposure to aristolochic acid I induces gastric histological lesions with non-specific renal injury in rat","volume":"68","author":"Pu","year":"2016","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.2174\/0929867311320220006","article-title":"Mechanisms of Herb-Induced Nephrotoxicity","volume":"20","author":"Allard","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1039\/c5tx00171d","article-title":"Screening and validation for plasma biomarkers of nephrotoxicity based on metabolomics in male rats","volume":"5","author":"Li","year":"2016","journal-title":"Toxicol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1099\/vir.0.81915-0","article-title":"Cell death in bovine parvovirus-infected embryonic bovine tracheal cells is mediated by necrosis rather than apoptosis","volume":"87","author":"Murray","year":"2006","journal-title":"J. Gen. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.envpol.2015.12.001","article-title":"Chronic exposure to microcystin-LR affected mitochondrial DNA maintenance and caused pathological changes of lung tissue in mice","volume":"210","author":"Li","year":"2016","journal-title":"Environ. Pollut."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1515\/jvetres-2017-0067","article-title":"MDA and GSH-Px Activity in Transition Dairy Cows Under Seasonal Variations and their Relationship with Reproductive Performance","volume":"61","author":"Colakoglu","year":"2017","journal-title":"J. Vet. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s12011-011-9271-y","article-title":"Selenium concentration and glutathione peroxidase (GSH-Px) activity in serum of cows at different stages of lactation","volume":"147","author":"Pilarczyk","year":"2012","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.2215\/CJN.11571017","article-title":"Nephrotoxicity and Chinese Herbal Medicine","volume":"13","author":"Yang","year":"2018","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"376","DOI":"10.3389\/fphar.2019.00376","article-title":"Application of Herbal Traditional Chinese Medicine in the Treatment of Acute Kidney Injury","volume":"10","author":"Li","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"569551","DOI":"10.3389\/fphar.2020.569551","article-title":"Nephrotoxicity of Herbal Medicine and Its Prevention","volume":"11","author":"Xu","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/978-94-007-2869-1_7","article-title":"The Mitochondrial Pathways of Apoptosis","volume":"Volume 942","author":"Scatena","year":"2012","journal-title":"Advances in Mitochondrial Medicine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1039\/C6TX00410E","article-title":"The UCP2-related mitochondrial pathway participates in rhein-induced apoptosis in HK-2 cells","volume":"6","author":"Mao","year":"2017","journal-title":"Toxicol. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1039\/c0ay00247j","article-title":"Detection of apoptosis: A review of conventional and novel techniques","volume":"2","author":"Martinez","year":"2010","journal-title":"Anal. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/1756-9966-30-87","article-title":"Apoptosis in cancer: From pathogenesis to treatment","volume":"30","author":"Wong","year":"2011","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1080\/10520295.2018.1521989","article-title":"Evaluation of apoptosis markers in different cell lines infected with equine arteritis virus","volume":"94","author":"Metz","year":"2019","journal-title":"Biotech. Histochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7795","DOI":"10.1021\/acs.jafc.5b02644","article-title":"Recombinant Buckwheat Trypsin Inhibitor Induces Mitophagy by Directly Targeting Mitochondria and Causes Mitochondrial Dysfunction in Hep G2 Cells","volume":"63","author":"Wang","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.tiv.2018.10.017","article-title":"Copper induces oxidative stress and apoptosis through mitochondria-mediated pathway in chicken hepatocytes","volume":"54","author":"Yang","year":"2019","journal-title":"Toxicol. Vitr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/ki.2012.264","article-title":"Probenecid prevents acute tubular necrosis in a mouse model of aristolochic acid nephropathy","volume":"82","author":"Baudoux","year":"2012","journal-title":"Kidney Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1038\/ki.2008.125","article-title":"Biotransformation enzymes in development of renal injury and urothelial cancer caused by aristolochic acid","volume":"73","author":"Stiborova","year":"2008","journal-title":"Kidney Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.etap.2013.07.017","article-title":"Tanshinone I protects mice from aristolochic acid I-induced kidney injury by induction of CYP1A","volume":"36","author":"Feng","year":"2013","journal-title":"Environ. Toxicol. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/toxsci\/kfr138","article-title":"Inhibition of renal NQO1 activity by dicoumarol suppresses nitroreduction of aristolochic acid I and attenuates its nephrotoxicity","volume":"122","author":"Chen","year":"2011","journal-title":"Toxicol. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1590\/S0004-27302011000400001","article-title":"The role of uncoupling protein 2 (UCP2) on the development of type 2 diabetes mellitus and its chronic complications","volume":"55","author":"Assmann","year":"2011","journal-title":"Arq. Bras. De Endocrinol. E Metabol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3674\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:44:28Z","timestamp":1760136268000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3674"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,27]]},"references-count":45,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ijms23073674"],"URL":"https:\/\/doi.org\/10.3390\/ijms23073674","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,27]]}}}