Ochratoxin A impairs Nrf2-dependent gene expression in porcine kidney tubulus cells
Ochratoxin A impairs Nrf2-dependent gene expression in porcine kidney tubulus cells
复制标题
DOI：
10.1111/j.1439-0396.2008.00838.x
复制
发表时间：
2009-10-01
影响因子：
2.7
通讯作者：
Rimbach, G.
中科院分区：
文献类型：
--
作者：
Boesch-Saadatmandi, C.;Wagner, A. E.;Rimbach, G.
赭曲霉毒素A（OTA）是由曲霉属和青霉属真菌产生的一种真菌毒素，常存在于饲料中。赭曲霉毒素A具有广泛的毒性，包括肾毒性。然而，OTA诱导的细胞肾毒性的潜在分子机制尚未完全阐明。Nrf 2是一种碱性亮氨酸拉链转录激活因子，对于肾脏中抗氧化剂和异生物质代谢酶的协调转录诱导至关重要。因此，在本研究中，OTA对核转位和转录因子Nrf 2的反式激活，以及Nrf 2的靶基因，包括谷胱甘肽-S-转移酶和γ-谷氨酰半胱氨酰合成酶的mRNA水平的影响，在培养的猪肾小管细胞（LLC-PK 1）进行了研究。nrf 2由萝卜硫素诱导，萝卜硫素是该转录因子的一种众所周知的激活剂。赭曲霉毒素A显着降低γ-谷氨酰半胱氨酰合成酶和谷胱甘肽-S-转移酶在LLC-PK 1细胞的mRNA水平。γ-谷氨酰半胱氨酰合成酶和谷胱甘肽-S-转移酶mRNA水平的降低伴随着Nrf 2核转位和反式激活的降低。此外，OTA还降低了Nrf 2 mRNA水平。目前的数据表明，OTA肾毒性可能，至少部分，介导的Nrf 2依赖性信号转导途径。
P>The mycotoxin, ochratoxin A (OTA), which is produced by Aspergillus and Penicillium subspecies, is frequently present in feedstuffs. Ochratoxin A exhibits a wide range of toxic activities including nephrotoxicity. However, the underlying molecular mechanisms of OTA-induced cellular nephrotoxicity have yet not been fully elucidated. Nrf2 is a basic leucine zipper transcriptional activator essential for the coordinated transcriptional induction of antioxidant and xenobiotic metabolizing enzymes in the kidney. Therefore, in the present study, the effects of OTA on the nuclear translocation and transactivation of the transcription factor Nrf2 as well as mRNA levels of Nrf2 target genes including glutathione-S-transferase and gamma-glutamylcysteinyl synthetase have been studied in cultured porcine kidney tubulus cells (LLC-PK1). Nrf2 was induced by sulforaphane, a well-known activator of this transcription factor. Ochratoxin A significantly decreased gamma-glutamylcysteinyl synthetase and glutathione-S-transferase mRNA levels in LLC-PK1 cells. Decreased mRNA levels of gamma-glutamylcysteinyl synthetase and glutathione-S-transferase were accompanied by a lowered nuclear translocation and transactivation of Nrf2. Furthermore, OTA also lowered Nrf2 mRNA levels. Current data indicate that OTA nephrotoxicity may be, at least partly, mediated by an Nrf2-dependent signal transduction pathway.