A new form of amphotericin B - the complex with copper (II) ions - downregulates sTNFR1 shedding and changes the activity of genes involved in TNF-induced pathways: AmB-Cu²⁺ downregulates sTNFR1 shedding and changes the activity of genes involved in TNF-induced pathways

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• 作者：Joanna Gola^a ; ^{jgola@sum.edu.pl} ; Barbara Strzałka-Mrozik^a ; Celina Kruszniewska-Rajs^a ; Adrian Janiszewski^a ; Bartłomiej Skowronek^a ; Mariusz Gagoś^b ; Grzegorz Czernel^c ; Urszula Mazurek^a
• 关键词：Amphotericin B ; Copper complexes ; Oligonucleotide microarrays ; Real-time RT-qPCR ; TNF
• 刊名：Pharmacological Reports
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：69
• 期：1
• 页码：22-28
• 全文大小：762 K
• 卷排序：69

文摘

A new form of amphotericin B (AmB)– complex with copper (II) ions (AmB–Cu2+) – is less toxic to human renal cells. Cytokines, including Tumor Necrosis Factor (TNF), are responsible for nephrotoxicity observed in patients treated with AmB. Another problem during therapy is the occurrence of oxidized forms of AmB (AmB-ox) in patients’ circulation. To elucidate the molecular mechanism responsible for the reduction of the toxicity of AmB–Cu2+, we evaluated the expression of genes encoding TNF and its receptors alongside encoding proteins involved in TNF-induced signalization.MethodsRenal cells (RPTECs) were treated with AmB, AmB–Cu2+ or AmB-ox. The expression of TNF and its receptors was evaluated by ELISA tests and real-time RT-qPCR. The expression of TNF-related genes was appointed using oligonucleotide microarrays.ResultsOnly sTNFR1 was detected, and its level was lower in AmB–Cu2+- and AmB-ox-treated cells. TNFR1 mRNA was downregulated in AmB-ox, while TNFR2 mRNA was upregulated in AmB and AmB–Cu2+. Several changes in the expression of TNF-related genes coincided with changes in the expression of TNF receptors.ConclusionsThe lower toxicity of AmB–Cu2+ could result from the changes in the expression of TNF receptors, which coincided with the changes in the expression of genes encoding proteins involved in TNF-induced pathways. This situation might subsequently result in a changes in intracellular signalization and influence the toxicity of tested forms of AmB on renal cells.