Neutral ceramidase deficiency protects against cisplatin-induced acute kidney injury

Sophia M. Sears, Tess V. Dupre, Parag P. Shah, Deanna L. Davis, Mark A. Doll, Cierra N. Sharp, Alexis A. Vega, Judit Megyesi, Levi J. Beverly, Ashley J. Snider, Lina M. Obeid, Yusuf A. Hannun, Leah J. Siskind

Research output: Contribution to journalArticlepeer-review

Abstract

Cisplatin is a commonly used chemotherapeutic for the treatment of many solid organ cancers; however, its effectiveness is limited by the development of acute kidney injury (AKI) in 30% of patients. AKI is driven by proximal tubule cell death, leading to rapid decline in renal function. It has previously been shown that sphingolipid metabolism plays a role in regulating many of the biological processes involved in cisplatin-induced AKI. For example, neutral ceramidase (nCDase) is an enzyme responsible for converting ceramide into sphingosine, which is then phosphorylated to become sphingosine-1-phosphate, and our lab previously demonstrated that nCDase knockout (nCDase¡/¡) in mouse embryonic fibroblasts led to resistance to nutrient and energy deprivation–induced cell death via upregulation of autophagic flux. In this study, we further characterized the role of nCDase in AKI by demonstrating that nCDase¡/¡ mice are resistant to cisplatin-induced AKI. nCDase¡/¡ mice display improved kidney function, reduced injury and structural damage, lower rates of apoptosis, and less ER stress compared to wild-type mice following cisplatin treatment. Although the mechanism of protection is still unknown, we propose that it could be mediated by increased autophagy, as chloroquine treatment resensitized nCDase¡/¡ mice to AKI development. Taken together, we conclude that nCDase may represent a novel target to prevent cisplatin-induced nephrotoxicity.

Original languageEnglish (US)
Article number100179
JournalJournal of Lipid Research
Volume63
Issue number3
DOIs
StatePublished - Mar 2022

Keywords

  • Animal models
  • Autophagy
  • Ceramide
  • Chemotherapy
  • Chloroquine
  • Cisplatin
  • ER stress
  • Renal disease
  • Sphingosine metabolism
  • Sphingosine-1-phosphate

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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