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

doi:10.1016/j.jlr.2022.100179

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.

Highlights

Cisplatin is a commonly used chemotherapeutic for the treatment of many solid organ cancers; its effectiveness is limited by the development of acute kidney injury (AKI) in 30% of patients
Neutral ceramidase is an enzyme involved in sphingolipid metabolism that cleaves ceramide into sphingosine, which is recycled back to ceramide or phosphorylated to become sphingosine-1-phosphate (S1P) [17–20]
NCDase¡/¡ mice are resistant to cisplatin-induced AKI

Summary

Introduction

Cisplatin is a commonly used chemotherapeutic for the treatment of many solid organ cancers; its effectiveness is limited by the development of acute kidney injury (AKI) in 30% of patients. As development of cisplatin-induced AKI is thought to be largely driven by cell death [4, 6], protecting proximal tubule cells from death is an attractive strategy to prevent kidney structural damage and maintain function. Sphingolipid metabolism in the kidney is recognized as a regulator of several cellular processes, including cell death, that play a role in the development of AKI and other renal diseases [12–14]; this connection has been explored by our lab. Neutral ceramidase (nCDase) is an enzyme involved in sphingolipid metabolism that cleaves ceramide into sphingosine, which is recycled back to ceramide or phosphorylated to become sphingosine-1-phosphate (S1P) [17–20] The balance of these three bioactive lipids is regulated by dynamic processes and is thought to play an important role in regulating cellular stress responses [15, 16]. We hypothesized that nCDase deficiency would prevent development of cisplatin-induced AKI via upregulation of autophagy and inhibition of cell death

Methods

Results

Conclusion