Lipidomics Reveals Cisplatin-Induced Renal Lipid Alterations during Acute Kidney Injury and Their Attenuation by Cilastatin.

Estefanía Moreno-Gordaliza,Alberto Lázaro,Óscar Pastor,Maria Dolores Marazuela,María Milagros Gómez-Gómez

doi:10.3390/ijms222212521

Abstract

Nephrotoxicity is a major complication of cisplatin-based chemotherapy, leading to acute kidney injury in ca. 30% of patients, with no preventive intervention or treatment available for clinical use. Cilastatin has proved to exert a nephroprotective effect for cisplatin therapies in in vitro and in vivo models, having recently entered clinical trials. A deeper understanding at the molecular level of cisplatin-induced renal damage and the effect of potential protective agents could be key to develop successful nephroprotective therapies and to establish new biomarkers of renal damage and nephroprotection. A targeted lipidomics approach, using LC-MS/MS, was employed for the quantification of 108 lipid species (comprising phospholipids, sphingolipids, and free and esterified cholesterol) in kidney cortex and medulla extracts from rats treated with cisplatin and/or cilastatin. Up to 56 and 63 lipid species were found to be altered in the cortex and medulla, respectively, after cisplatin treatment. Co-treatment with cilastatin attenuated many of these lipid changes, either totally or partially with respect to control levels. Multivariate analysis revealed that lipid species can be used to discriminate renal damage and nephroprotection, with cholesterol esters being the most discriminating species, along with sulfatides and phospholipids. Potential diagnostic biomarkers of cisplatin-induced renal damage and cilastatin nephroprotection were also found.

Highlights

Nephrotoxicity is a serious side effect of cisplatin chemotherapy [1], with acute kidney injury (AKI) being developed in ca. 30% of the treated patients [2]
We have quantified a total of 108 lipid species comprising important structural lipids such as phospholipids, sphingolipids, and cholesterol along with its esterified forms, on the kidney cortex and medulla from rats treated with cisplatin and/or cilastatin
Up to 63 lipid species were found to be significantly altered in the medulla by cisplatin treatment, while 56 lipid species were affected in the cortex, reflecting renal damage in both regions

Summary

Introduction

Nephrotoxicity is a serious side effect of cisplatin chemotherapy [1], with acute kidney injury (AKI) being developed in ca. 30% of the treated patients [2]. A series of cellular events take place in relation to renal tubule cell injury, following cisplatin uptake, including oxidative stress, nitrosative stress, vascular injury, inflammation, mitochondrial damage or inhibition of Na+, K+ATPase in the cell membrane, and endoplasmic reticulum stress, followed by proximal tubule cell death mainly by apoptosis (both involving intrinsic and extrinsic pathways) or necrosis, leading to loss of renal function [2,6,7]. This is manifested in the decrease in the glomerular filtration rate (GFR) and serum magnesium and potassium levels, with increased blood urea nitrogen (BUN) and serum creatinine [2]

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Results

Conclusion