Expression profiles of genes related to melatonin and oxidative stress in human renal proximal tubule cells treated with antibiotic amphotericin B and its modified forms

Authors: JOANNA GOLA, ALEKSANDRA SKUBIS, BARTOSZ SIKORA, CELINA KRUSZNIEWSKA-RAJS, JOLANTA ADAMSKA, URSZULA MAZUREK, BARBARA STRZALKA-MROZIK, GRZEGORZ CZERNEL, MARIUSZ GAGOS

Abstract: Melatonin protects cells from oxidative stress caused by antibiotics. Through the generation of reactive oxygen species (ROS), amphotericin B (AmB) causes oxidative injuries of the kidneys and liver. Generation of oxidized forms of AmB (AmB-ox) in a patient's circulation may also generate ROS, causing side effects. Studies aimed at elimination of toxic properties of AmB are focused on forming complexes of AmB with copper(II) ions (AmB-Cu²⁺). However, the influence of such modified forms on renal cells and their transcriptome has not been studied so far. Therefore, the aim of this study was to answer the question of whether AmB-Cu²⁺ complexes and AmB-ox influence the transcriptional activity of melatonin-related and oxidative stress-related genes in human renal proximal tubule epithelial cells (RPTECs) and whether these changes can result in less toxicity of modified forms of AmB. Gene expression profile was evaluated with the use of oligonucleotide microarrays. At high concentrations AmB-Cu²⁺ was two times less toxic than AmB and AmB-ox. AmB-Cu²⁺ caused downregulation of oxidative stress-related genes and RORA, and upregulation of AANAT and MTNR1B. AmB-ox caused similar molecular changes. Based on cytotoxicity tests results and changes in melatonin- and oxidative stress-related genes expression profiles, we conclude that AmB-Cu²⁺ is less toxic for RPTECs.

Keywords: Amphotericin B, copper complexes, oxidative stress, melatonin, oligonucleotide microarrays

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