Amphotericin B-copper (II) complex alters transcriptional activity of genes encoding transforming growth factor-beta family members and related proteins in renal cells

Background: Several chemical modifications have been developed to overcome the toxicity of amphotericin B (AmB). Oxidized forms of AmB (AmB-ox), which may occur in patient's circulation during therapy, are as toxic as AmB. Complexes with copper (II) ions (AmB-Cu2+) have been reported to be less toxic to human cells. Previous studies showed that AmB changed the expression of transforming growth factor-beta (TGF-beta). Therefore, the objective of this study was to investigate the influence of AmB and its modified forms on the expression of genes encoding for TGF-beta family members and related proteins in renal cells. Methods: Human renal proximal tubule cells (RPTEC) were treated with AmB-Cu2+, AmB, or the oxidized form AmB-ox. The expression of TGF-beta family members and related genes was determined using oligonucleotide microarrays. TGF-beta 1 protein level was determined using ELISA method. The mRNA level of TGF-beta isoforms, TGF-beta receptors and differentiating genes was evaluated by real-time RT-qPCR. Results: AmB-Cu2+ increased the mRNA levels of TGF-beta 1 and TGF-beta 2 isoforms and two genes encoding receptors: TGFBR1 and TGFBR2. TGF-beta 1 protein level in culture medium was not increased after stimulation with AmB-Cu2+. Microarray analysis revealed changes in both pro-fibrotic and anti-fibrotic genes. Conclusions: These results suggest that AmB-Cu2+ may induce repair mechanisms in renal proximal tubule cells via changes in the expression of genes involved in intracellular signaling. (c) 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.