Lipid imaging for visualizing cilastatin amelioration of cisplatin-induced nephrotoxicity

Abstract

Nephrotoxicity is a major limitation to cisplatin antitumor therapies. Cilastatin, an inhibitor of renal dehydropeptidase-I, was recently proposed as a promising nephroprotector against cisplatin toxicity, preventing apoptotic cell death. In this work, cilastatin nephroprotection was further investigated in a rat model, with a focus on its effect on 76 renal lipids altered by cisplatin, including 13 new cisplatin-altered mitochondrial cardiolipin species. Lipid imaging was performed with MALDI mass spectrometry imaging (MALDI-MSI) in kidney sections from treated rats. Cilastatin was proved to significantly diminish the lipid distribution alterations caused by cisplatin, lipid levels being almost completely recovered to those of control samples. The extent of recovery of cisplatin-altered lipids by cilastatin turned out to be relevant for discriminating direct or secondary lipid alterations driven by cisplatin. Lipid peroxidation induced by cisplatin was also shown to be reduced when cilastatin was administered. Importantly, significant groups separation was achieved during multivariate analysis of cortex and outer-medullary lipids, indicating that damaged kidney can be discerned from the nephroprotected and healthy groups and classified according to lipid distribution. Therefore, we propose MALDI-MSI as a powerful potential tool offering multimolecule detection possibilities to visualize and evaluate nephrotoxicity and nephroprotection based on lipid analysis.

Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study

“…Interestingly, for cilastatin-induced kidney toxicity in an animal model, lipid imaging was performed by MALDI mass spectrometry of kidney sections. In the study, statin therapy successfully lowered the lipid distribution, which had previously been induced by cisplatin toxicity, and decreased the lipid peroxidation capacity, with statin showing no effect on the lipid distribution in the normal control [ 49 ]. This paper described a new link in the pathology between AKI and the lipid distribution.…”

Myricetin Abrogates Cisplatin-Induced Oxidative Stress, Inflammatory Response, and Goblet Cell Disintegration in Colon of Wistar Rats

“…In our study, the protective properties of myricetin are speculated to be linked with mitigating oxidative and inflammatory response in the colon of experimental animals. Cisplatin administration creates hydroxyl radical (•OH), superoxide anion (O2•−), and hydrogen peroxide (H 2 O 2 ), which play a crucial role in the instigation of lipid peroxidation [59]. Chang et al (2002) [60] reported that cisplatin treatment initiates an autocatalytic lipid peroxidation reaction that amplifies the levels of fatty acids in the mucosal layer of the intestine.…”

Kidney Lipidomics by Mass Spectrometry Imaging: A Focus on the Glomerulus

“…MSI lipidomics has extensively been performed on rodent material by matrix-assisted laser desorption/ionization (MALDI), the mainstream method for MSI, which is characterized by the addition of an organic chemical matrix on biological specimens. This technology has been used on normal tissue [19,20,21,22,23] and in different pathophysiologic contexts, such as acute renal injury [24], diabetes/obesity [25], renal acidosis [26] polycystic kidney [27], drug-induced nephrotoxicity [28,29], bisphenol toxicity [30], polymyxin toxicity [31], Fabry disease [32,33], and in glomerulopathies, such as diabetic nephropathy [34] and IgA nephropathy [35].…”