Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury
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J.Lipid Res.-2017-Dupre-1439-52.pdf
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Author
Dupre, Tess V.Doll, Mark A.
Shah, Parag P.
Sharp, Cierra N.
Siow, Deanna
Megyesi, Judit
Shayman, James
Bielawska, Alicja
Bielawski, Jacek
Beverly, Levi J.
Hernandez-Corbacho, Maria
Clarke, Christopher J.
Snider, Ashley J.
Schnellmann, Rick G.
Obeid, Lina M.
Hannun, Yusuf A.
Siskind, Leah J.
Affiliation
Univ Arizona, Coll Pharm, Dept Pharmacol & ToxicolIssue Date
2017-07
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Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury 2017, 58 (7):1439 Journal of Lipid ResearchJournal
Journal of Lipid ResearchRights
Copyright © 2017, by the American Society for Biochemistry and Molecular Biology.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
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.Note
12 month embargo; Published online: May 10, 2017,ISSN
0022-22751539-7262
Version
Final published versionSponsors
National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK093462]; National Institutes of Health [P30 CA138313, P20RR017677, UH2NS092981, 1R01HD076004-04, GM097741, PO1CA097132]; Veterans Affairs Merit Awards [1I01BX002021-04, CAMM-011-13S]Additional Links
http://www.jlr.org/lookup/doi/10.1194/jlr.M076745ae974a485f413a2113503eed53cd6c53
10.1194/jlr.M076745