Subcellular Renal Proximal Tubular Mitochondrial Toxicity with Tenofovir Treatment
Subcellular Renal Proximal Tubular Mitochondrial Toxicity with Tenofovir Treatment
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DOI：
10.1007/978-1-61779-163-5_22
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Hosseini, Seyed H.
中科院分区：
文献类型：
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作者：
Kohler, James J.;Hosseini, Seyed H.
核苷逆转录酶抑制剂（NRTI）是用于治疗艾滋病毒/艾滋病的药物。尽管基于NRTI的治疗具有明显的益处，但组织特异性毒性是一个限制因素。尽管这些特异性抗逆转录病毒药物相关毒性的机制尚不清楚，但据推测，作为天然核苷的类似物，NRTI可能潜在地抑制哺乳动物DNA聚合酶，包括线粒体DNA（mtDNA）聚合酶γ。富马酸替诺福韦酯（TDF）是腺苷酸的核苷酸类似物，也是唯一与肾脏疾病相关的NRTI。肾组织的固有异质性可能影响分子研究的结果和解释，以确定替诺福韦肾小管毒性的机制。激光捕获显微切割（LCM）提供了一个特定的，单细胞分离近端小管从固定的异质性肾组织。LCM捕获的转基因小鼠（TG）的肾近端小管显示替诺福韦减少mtDNA丰度，证明了艾滋病模型中替诺福韦的亚细胞特异性线粒体毒性。
Nucleoside reverse transcriptase inhibitors (NRTIs) are drugs used in the treatment of HIV/AIDS. Despite the distinct benefits of NRTI-based therapies, tissue specific toxicity is a limiting factor. Although the mechanisms of these specific antiretroviral drug-related toxicities remain unclear, it has been hypothesized that as analogs to native nucleosides, NRTIs may potentially inhibit mammalian DNA polymerases, including mitochondrial DNA (mtDNA) polymerase gamma. Tenofovir disoproxil fumarate (TDF) is a nucleotide analog of adenosine monophosphate and the only NRTI that is associated with renal disease. The inherent heterogeneity of kidney tissues could affect the outcome and interpretation of molecular studies to define the mechanism(s) of tenofovir tubular toxicity. Laser-capture microdissection (LCM) provided a specific, single-cell isolation of proximal tubules from fixed heterogeneous kidney tissues. LCM-captured renal proximal tubules from transgenic mice (TGs) showed decreased mtDNA abundance with tenofovir, demonstrating a subcellular specific mitochondrial toxicity of tenofovir in an AIDS model.