Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury

Tess V. Dupre, Mark A. Doll, Parag P. Shah, Cierra N. Sharp, Deanna Siow, Judit Megyesi, James Shayman, Alicja Bielawska, Jacek Bielawski, Levi J. Beverly, Maria Hernandez-Corbacho, Christopher J. Clarke, Ashley J. Snider, Rick G. Schnellmann, Lina M. Obeid, Yusu A. Hannun, Leah J. Siskind

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Acute kidney injury (AKI), resulting from chemo-therapeutic agents such as cisplatin, remains an obstacle in the treatment of cancer. Cisplatin-induced AKI involves apop-totic and necrotic cell death, pathways regulated by sphingolipids such as ceramide and glucosylceramide. Results from this study indicate that C57BL/6J mice treated with cisplatin had increased ceramide and hexosylceramide levels in the renal cortex 72 h following cisplatin treatment. Pretreatment of mice with inhibitors of acid sphingomyelinase and de novo ceramide synthesis (amitriptyline and myriocin, respectively) prevented accumulation of ceramides and hexosylceramide in the renal cortex and protected from cisplatin-induced AKI. To determine the role of ceramide metabolism to hexo-sylceramides in kidney injury, we treated mice with a potent and highly specific inhibitor of glucosylceramide synthase, the enzyme responsible for catalyzing the glycosylation of ceramides to form glucosylceramides. Inhibition of glucosylceramide synthase attenuated the accumulation of the hexo-sylceramides and exacerbated ceramide accumulation in the renal cortex following treatment of mice with cisplatin. Increasing ceramides and decreasing glucosylceramides in the renal cortex sensitized mice to cisplatin-induced AKI according to markers of kidney function, kidney injury, inflammation, cell stress, and apoptosis. Under conditions of high ceramide generation, data suggest that metabolism of ceramides to glucosylceramides buffers kidney ceramides and helps attenuate kidney injury.

Original languageEnglish (US)
Pages (from-to)1439-1452
Number of pages14
JournalJournal of Lipid Research
Volume58
Issue number7
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • Apoptosis
  • Ceramide
  • Inflammation
  • Sphingolipids

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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