PMID- 35151662 OWN - NLM STAT- MEDLINE DCOM- 20220405 LR - 20240425 IS - 1539-7262 (Electronic) IS - 0022-2275 (Print) IS - 0022-2275 (Linking) VI - 63 IP - 3 DP - 2022 Mar TI - Neutral ceramidase deficiency protects against cisplatin-induced acute kidney injury. PG - 100179 LID - S0022-2275(22)00012-8 [pii] LID - 10.1016/j.jlr.2022.100179 [doi] LID - 100179 AB - 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. CI - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Sears, Sophia M AU - Sears SM AD - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY, USA. FAU - Dupre, Tess V AU - Dupre TV AD - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY, USA. FAU - Shah, Parag P AU - Shah PP AD - Department of Medicine, University of Louisville, Louisville, KY, USA; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Davis, Deanna L AU - Davis DL AD - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY, USA. FAU - Doll, Mark A AU - Doll MA AD - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY, USA. FAU - Sharp, Cierra N AU - Sharp CN AD - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY, USA. FAU - Vega, Alexis A AU - Vega AA AD - Department of Biochemistry & Molecular Genetics, University of Louisville, Louisville, KY, USA. FAU - Megyesi, Judit AU - Megyesi J AD - Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas, Veterans Healthcare System, Little Rock, AR, USA. FAU - Beverly, Levi J AU - Beverly LJ AD - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY, USA; Department of Medicine, University of Louisville, Louisville, KY, USA; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Snider, Ashley J AU - Snider AJ AD - Department of Nutritional Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ, USA. FAU - Obeid, Lina M AU - Obeid LM AD - Department of Medicine, Stony Brook University, Stony Brook, NY, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA; Northport Veteran Affairs Medical Center, Northport, NY, USA. FAU - Hannun, Yusuf A AU - Hannun YA AD - Department of Medicine, Stony Brook University, Stony Brook, NY, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA; Northport Veteran Affairs Medical Center, Northport, NY, USA. FAU - Siskind, Leah J AU - Siskind LJ AD - Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY, USA; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. Electronic address: leah.siskind@louisville.edu. LA - eng GR - R01 CA218678/CA/NCI NIH HHS/United States GR - R01 DK124112/DK/NIDDK NIH HHS/United States GR - P01 CA097132/CA/NCI NIH HHS/United States GR - R35 GM118128/GM/NIGMS NIH HHS/United States GR - F31 DK126400/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20220210 PL - United States TA - J Lipid Res JT - Journal of lipid research JID - 0376606 RN - EC 3.5.1.23 (Neutral Ceramidase) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - *Acute Kidney Injury/chemically induced/prevention & control MH - Animals MH - Apoptosis/physiology MH - Cisplatin/adverse effects MH - *Farber Lipogranulomatosis MH - Fibroblasts/metabolism MH - Humans MH - Mice MH - Neutral Ceramidase/metabolism PMC - PMC8953688 OTO - NOTNLM OT - ER stress OT - animal models OT - autophagy OT - ceramide OT - chemotherapy OT - chloroquine OT - cisplatin OT - renal disease OT - sphingosine metabolism OT - sphingosine-1-phosphate COIS- Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. EDAT- 2022/02/14 06:00 MHDA- 2022/04/05 06:00 PMCR- 2022/02/10 CRDT- 2022/02/13 20:28 PHST- 2022/01/18 00:00 [received] PHST- 2022/02/02 00:00 [revised] PHST- 2022/02/03 00:00 [accepted] PHST- 2022/02/14 06:00 [pubmed] PHST- 2022/04/05 06:00 [medline] PHST- 2022/02/13 20:28 [entrez] PHST- 2022/02/10 00:00 [pmc-release] AID - S0022-2275(22)00012-8 [pii] AID - 100179 [pii] AID - 10.1016/j.jlr.2022.100179 [doi] PST - ppublish SO - J Lipid Res. 2022 Mar;63(3):100179. doi: 10.1016/j.jlr.2022.100179. Epub 2022 Feb 10.