Acute kidney injury (AKI), resulting from chemotherapeutic agents such as
cisplatin, remains an obstacle in the treatment of
cancer.
Cisplatin-induced AKI involves apoptotic 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 hexosylceramides 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 hexosylceramides 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.-Dupre, T. V., M. A. Doll, P. P. Shah, C. N. Sharp, D. Siow, J. Megyesi, J. Shayman, A. Bielawska, J. Bielawski, L. J. Beverly, M. Hernandez-Corbacho, C. J. Clarke, A. J. Snider, R. G. Schnellmann, L. M. Obeid, Y. A. Hannun, and L. J. Siskind. Inhibiting
glucosylceramide synthase exacerbates
cisplatin-induced
acute kidney injury. J.
Lipid Res 2017. 58: 1439-1452.