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

ABSTRACT

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-ß). 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-ß 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-ß family members and related genes was determined using oligonucleotide microarrays. TGF-ß1 protein level was determined using ELISA method. The mRNA level of TGF-ß isoforms, TGF-ß receptors and differentiating genes was evaluated by real-time RT-qPCR. RESULTS: AmB-Cu2+ increased the mRNA levels of TGF-ß1 and TGF-ß2 isoforms and two genes encoding receptors TGFBR1 and TGFBR2. TGF-ß1 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.