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Kidney Week

Abstract: PO0226

Neutral Ceramidase and Autophagy Play Diverse Roles in Cisplatin-Induced AKI and Fibrosis

Session Information

  • AKI Mechanisms - 3
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Sears, Sophia Marie, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Dupre, Tess, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Doll, Mark A., University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Shah, Parag P., University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Beverly, Levi J., University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Siskind, Leah J., University of Louisville School of Medicine, Louisville, Kentucky, United States
Background

Cisplatin (CDDP) is a commonly used chemotherapeutic agent with a dose-limiting nephrotoxicity. 30% of patients given CDDP develop acute kidney injury (AKI), increasing risk of chronic kidney disease (CKD) development and mortality. Currently, there are no agents to treat or prevent CDDP-induced kidney injury. We believe this is due in part to a lack of clinically relevant animal models. In the past, only a single high-dose model has been used to study CDDP-induced AKI. Our lab and others have developed a repeated low dose model to also study CKD development following CDDP treatment. Acute and chronic injuries can both be affected by sphingolipids, a family of bioactive lipids. Metabolism of sphingolipids is carried out in part by neutral ceramidase (nCDase), which hydrolyzes ceramide into sphingosine that can then be phosphorylated to form sphingosine-1-phosphate. The regulation of these sphingolipids affects cellular processes implicated in the pathology of CDDP-induced kidney injury, including cell proliferation, autophagy, and apoptosis. Additionally, our lab has previously observed that nDCase knockout protected mouse embryonic fibroblasts from ER-stress induced apoptosis in vitro by upregulating autophagic flux. We hypothesized that loss of nCDase would confer protection from CDDP-induced kidney injury.

Methods

We assessed renal outcomes in nCDase knockout (KO) and wild type (WT) C57BL/6 mice in both the acute and chronic models of cisplatin treatment.

Results

We demonstrated that nCDase KO provides protection from AKI in the high-dose model of CDDP-induced kidney injury. This protection was reversed when the autophagy-inhibitor chloroquine was co-administered. In the repeated low dose CDDP model, however, we found nCDase KO does not protect against development of renal fibrosis. We also observed that nCDase KO reduces induction of ER stress in the single high-dose model but not in the repeated low dose model.

Conclusion

This study suggests that there are different underlying mechanisms that induce divergent pathologies in the two models of CDDP dosing.

Funding

  • NIDDK Support