Zoledronic acid‐induced oxidative damage and endoplasmic reticulum stress‐mediated apoptosis in human embryonic kidney (HEK‐293) cells

Journal of Biochemical and Molecular ToxicologyEarly View e23083 RESEARCH ARTICLE Zoledronic acid-induced oxidative damage and endoplasmic reticulum stress-mediated apoptosis in human embryonic kidney (HEK-293) cells Mehtap Kara, Mehtap Kara Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySearch for more papers by this authorTuğçe Boran, Tuğçe Boran Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySearch for more papers by this authorEzgi Öztaş, Ezgi Öztaş Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySearch for more papers by this authorAyse Tarbin Jannuzzi, Ayse Tarbin Jannuzzi Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySearch for more papers by this authorSibel Özden, Sibel Özden Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySearch for more papers by this authorGül Özhan, Corresponding Author Gül Özhan gulozhan@istanbul.edu.tr Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey Correspondence Gül Özhan, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Beyazit, 34116 Istanbul, Turkey. Email: gulozhan@istanbul.edu.trSearch for more papers by this author Mehtap Kara, Mehtap Kara Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySearch for more papers by this authorTuğçe Boran, Tuğçe Boran Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySearch for more papers by this authorEzgi Öztaş, Ezgi Öztaş Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySearch for more papers by this authorAyse Tarbin Jannuzzi, Ayse Tarbin Jannuzzi Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySearch for more papers by this authorSibel Özden, Sibel Özden Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySearch for more papers by this authorGül Özhan, Corresponding Author Gül Özhan gulozhan@istanbul.edu.tr Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey Correspondence Gül Özhan, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Beyazit, 34116 Istanbul, Turkey. Email: gulozhan@istanbul.edu.trSearch for more papers by this author First published: 19 May 2022 https://doi.org/10.1002/jbt.23083Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Zoledronic acid, a nitrogen-containing bisphosphonate drug, is used for the treatment of osteoporosis, Paget's disease of bone, and tumor-induced osteolysis. Zoledronic acid has also gained a place in cancer treatment due to its cytotoxic and antiproliferative effects in many cancer cells. Although zoledronic acid is considered safe, kidney damage is still one of the concerns in therapeutic doses. In the study, the aim was to assess the nephrotoxic profiles of zoledronic acid in the human embryonic kidney (HEK-293) cells. Cytotoxicity evaluation was performed by 3-[4,5-dimethylthiazol-2-yl]−2,5-diphenyl-tetrazolium bromide (MTT) and neutral red uptake tests, while oxidative stress was performed by reactive oxygen species (ROS) production via flow cytometry, and the incomprehensible evaluation of ROS-related genes by RT-PCR and apoptosis was performed with Annexin-PI analysis in flow cytometry. The obtained result showed that zoledronic acid inhibited cell viability (IC50 values were determined as 273.16 by MTT) and cell proliferation in a concentration-dependent manner, induced ROS production, caused glutathione depletion, and increased oxidative stress index and endoplasmic reticulum (ER) stress, indicating severe cellular stress. The expression levels of oxidative damage (L-fabp, α-GST, Nrf2, and HMOX1), ER stress (CASP4, IRE1-α, GADD153, and GRP78), and apoptosis (Bcl-2, Bax, Cyt-c, p53, CASP9, CASP3, NF-κB, TNF-α, and JNK) related genes were altered as well as IRE1-α protein levels. Herein, we were the first to show that increased oxidative stress and ER stress resulting in apoptosis are the key molecular pathways in zoledronic acid-induced nephrotoxicity equivalent to clinically administered concentrations. Open Research DATA AVAILABILITY STATEMENT All data generated or analyzed during this study are included in this article. Early ViewOnline Version of Record before inclusion in an issuee23083 RelatedInformation