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

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.

ROS-responsive curcumin-encapsulated nanoparticles for AKI therapy via promoting lipid degradation in renal tubules

“…The development and progression of AKI are associated with ectopic lipid deposition in the kidneys, and targeted reduction of renal lipid accumulation may significantly alleviate AKI pathology. 1–3 Previous studies have shown that ischemia-reperfusion-induced and cisplatin-induced AKI models produced significant ectopic lipid deposition in renal proximal tubular cells, 1,4–6 indicating that promotion of lipid degradation could alleviate AKI pathology. Thus, developing therapeutic approaches to reduce tubular cell lipid accumulation may be a promising strategy for combating AKI progression and severity.…”

Special Issue “Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0”

“…The search for successful nephroprotective agents and new biomarkers of renal damage and nephroprotection has led to cilastatin, which has proved, in vitro and in vivo, to exert a nephroprotective effect in cisplatin therapies, recently entering clinical trials. Moreno-Gordaliza and co-workers have used a targeted lipidomics approach, using LC-MS/MS, for the quantification of 108 lipid species (including phospholipids, sphingolipids, and free and esterified cholesterol) in kidney cortex and medulla extracts from rats treated with cisplatin and/or cilastatin [7]. The results have shown, after cisplatin treatment, an alteration in the cortex and medulla up to 56 and 63 lipid species, respectively.…”