Magnesium protects against cisplatin-induced acute kidney injury by regulating platinum accumulation

Am J Physiol Renal Physiol. 2014 Aug 15;307(4):F369-84. doi: 10.1152/ajprenal.00127.2014. Epub 2014 Jun 18.


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.

Keywords: apoptosis; hypomagnesemia; inflammation; nephrotoxicity; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control
  • Animals
  • Antineoplastic Agents / adverse effects*
  • Apoptosis / drug effects
  • Blood Urea Nitrogen
  • Cell Line, Tumor
  • Cisplatin / adverse effects*
  • Creatinine / blood
  • Cytokines / biosynthesis
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Kidney / metabolism
  • LLC-PK1 Cells
  • Magnesium / metabolism
  • Magnesium / therapeutic use*
  • Magnesium Deficiency / physiopathology
  • Mice
  • Neutrophil Infiltration / drug effects*
  • Oxidative Stress / drug effects
  • Platinum / metabolism
  • STAT3 Transcription Factor / metabolism
  • Swine


  • Antineoplastic Agents
  • Cytokines
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Platinum
  • Creatinine
  • Extracellular Signal-Regulated MAP Kinases
  • Magnesium
  • Cisplatin