Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation

J Pharmacol Sci. 2015 Jan;127(1):117-26. doi: 10.1016/j.jphs.2014.11.009. Epub 2014 Dec 4.


Cisplatin is a chemotherapeutic drug but induces acute kidney injury (AKI). Cisplatin-induced AKI depends on several signaling pathways leading to apoptosis in tubular epithelial cells. Glutamine is a substrate for the synthesis of glutathione, the most abundant intracellular thiol and antioxidant, and plays an important role in protecting cells from apoptosis induced by different stimuli. In the present study, we investigated the protective effect of glutamine on cisplatin-induced AKI. Rats were divided into control, glutamine, cisplatin, and cisplatin plus glutamine groups. Glutamine ameliorated renal dysfunction, tissue injury, and cisplatin-induced apoptosis. Cisplatin increased cell death, caspase-3 cleavage, activation of MAPKs and p53, oxidative stress, and mRNA expression of TNF-α and TNFR1 in HK-2 cells. Glutamine treatment reduced cisplatin-induced these changes in HK-2 cells. Notably, glutamine reduced the cisplatin-induced expression of organic cation transporter 2 (OCT2) and cisplatin accumulation. Our results suggest that the protective effect of glutamine on cisplatin is specific for proximal tubular cells and the initial effects may be related to attenuation of cisplatin uptake. Thus, glutamine administration might represent a new strategy for the treatment of cisplatin-induced AKI.

Keywords: Acute kidney injury; Cisplatin; Cisplatin uptake; Glutamine; Nephrotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Death / drug effects
  • Cell Line
  • Cisplatin / adverse effects
  • Cisplatin / metabolism*
  • Glutamine / pharmacology*
  • Glutathione / metabolism
  • Humans
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Male
  • Organic Cation Transport Proteins / biosynthesis
  • Organic Cation Transporter 2
  • Oxidative Stress / drug effects
  • Rats
  • Receptors, Tumor Necrosis Factor, Type I / biosynthesis
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • Receptors, Tumor Necrosis Factor, Type I
  • SLC22A2 protein, human
  • Tumor Necrosis Factor-alpha
  • Glutamine
  • Caspase 3
  • Glutathione
  • Cisplatin