title: Magnesium protects against cisplatin-induced acute kidney injury by regulating platinum accumulation.
abstract: Despite its success as a potent antineoplastic agent, ∼25% of patients receiving cisplatin experience acute kidney injury (AKI) and must discontinue therapy. Impaired magnesium homeostasis has been linked to cisplatin-mediated AKI, and because magnesium deficiency is widespread, we examined the effect of magnesium deficiency and replacement on cisplatin-induced AKI in physiologically relevant older female mice. Magnesium deficiency significantly increased cisplatin-associated weight loss and markers of renal damage (plasma blood urea nitrogen and creatinine), histological changes, inflammation, and renal cell apoptosis and modulated signaling pathways (e.g., ERK1/2, p53, and STAT3). Conversely, these damaging effects were reversed by magnesium. Magnesium deficiency alone significantly induced basal and cisplatin-mediated oxidative stress, whereas magnesium replacement attenuated these effects. Similar results were observed using cisplatin-treated LLC-PK1 renal epithelial cells exposed to various magnesium concentrations. Magnesium deficiency significantly amplified renal platinum accumulation, whereas magnesium replacement blocked the augmented platinum accumulation after magnesium deficiency. Increased renal platinum accumulation during magnesium deficiency was accompanied by reduced renal efflux transporter expression, which was reversed by magnesium replacement. These findings demonstrate the role of magnesium in regulating cisplatin-induced AKI by enhancing oxidative stress and thus promoting cisplatin-mediated damage. Additional in vitro experiments using ovarian, breast, and lung cancer cell lines showed that magnesium supplementation did not compromise cisplatin's chemotherapeutic efficacy. Finally, because no consistently successful therapy to prevent or treat cisplatin-mediated AKI is available for humans, these results support developing more conservative magnesium replacement guidelines for reducing cisplatin-induced AKI in cancer patients at risk for magnesium deficiency.
authors.affiliation: Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; The Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and.
authors.forename: Malvika H
authors.initials: MH
authors.lastname: Solanki
authors.affiliation: The Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and.
authors.forename: Prodyot K
authors.initials: PK
authors.lastname: Chatterjee
authors.affiliation: Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; The Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and.
authors.forename: Madhu
authors.initials: M
authors.lastname: Gupta
authors.affiliation: The Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and.
authors.forename: Xiangying
authors.initials: X
authors.lastname: Xue
authors.affiliation: The Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and.
authors.forename: Andrei
authors.initials: A
authors.lastname: Plagov
authors.affiliation: The Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and cmetz@nshs.edu.
authors.forename: Margot H
authors.initials: MH
authors.lastname: Metz
authors.affiliation: The Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Mintz
authors.affiliation: The Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and Hofstra North Shore-LIJ School of Medicine, Manhasset, New York.
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
authors.affiliation: Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; The Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and Hofstra North Shore-LIJ School of Medicine, Manhasset, New York.
authors.forename: Christine N
authors.initials: CN
authors.lastname: Metz
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000009:adverse effects*; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D018374:LLC-PK1 Cells; D008274:Magnesium / Q000378:metabolism / Q000627:therapeutic use*; D008275:Magnesium Deficiency / Q000503:physiopathology; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D010984:Platinum / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013552:Swine
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D010984:Platinum; D003404:Creatinine; D048049:Extracellular Signal-Regulated MAP Kinases; D008274:Magnesium; D002945:Cisplatin
keywords: apoptosis; hypomagnesemia; inflammation; nephrotoxicity; oxidative stress