Chronic alcohol exposure negatively impacts the physiological and molecular parameters of the renal biotin reabsorption process.
Chronic alcohol exposure negatively impacts the physiological and molecular parameters of the renal biotin reabsorption process.
复制标题
慢性酒精暴露会对肾脏生物素重吸收过程的生理和分子参数产生负面影响。
DOI：
10.1152/ajprenal.00707.2010
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Said,HamidM
中科院分区：
文献类型：
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作者：
Subramanian,VeedamaliS;Subramanya,SandeepB;Said,HamidM
生物素的正常体内平衡主要依赖于肾脏近端肾小管上皮细胞对生物素的恢复，这一过程由钠依赖性多种维生素转运蛋白（SMVT; SLC 5A 6基因的产物）介导。慢性酒精消耗干扰肾脏对多种营养物质的重吸收过程，包括水溶性维生素。然而，到目前为止，还没有任何关于长期酒精喂养对肾脏生物素重吸收过程的生理和分子参数的影响。我们使用携带人SLC 5A 6（P1 P2）5′-调控区的大鼠和转基因小鼠作为酒精暴露的体内模型系统，并将培养的人近端肾小管上皮细胞HK-2长期暴露于酒精作为酒精暴露的体外模型。[3 H]生物素摄取结果表明，大鼠慢性乙醇喂养导致载体介导的生物素跨肾刷状缘和基底外侧膜域转运的显著抑制。这种抑制与SMVT蛋白、mRNA和异源核RNA（hnRNA）表达水平的显著降低相关。此外，对携带SLC 5A 65 ′调控区的转基因小鼠的研究表明，长期酒精喂养导致启动子活性显著降低。对HK-2细胞长期暴露于酒精的研究再次显示，载体介导的生物素摄取显著减少，这与人SLC 5A 65 ′调控区启动子活性的显著降低有关。这些研究结果首次表明，慢性乙醇喂养抑制肾脏生物素转运，这种影响是，至少部分地，在转录水平上发挥。
Normal body homeostasis of biotin is critically dependent on its renal recovery by kidney proximal tubular epithelial cells, a process that is mediated by the sodium-dependent multivitamin transporter (SMVT; a product of theSLC5A6gene). Chronic ethanol consumption interferes with the renal reabsorption process of a variety of nutrients, including water-soluble vitamins. To date, however, there is nothing known about the effect of chronic alcohol feeding on physiological and molecular parameters of the renal biotin reabsorption process. We addressed these issues using rats and transgenic mice carrying the humanSLC5A6(P1P2) 5′-regulatory region as an in vivo model systems of alcohol exposure, and cultured human renal proximal tubular epithelial HK-2 cells chronically exposed to alcohol as an in vitro model of alcohol exposure. The [3H]biotin uptake results showed that chronic ethanol feeding in rats leads to a significant inhibition in carrier-mediated biotin transport across both renal brush border and basolateral membrane domains. This inhibition was associated with a marked reduction in the level of expression of SMVT protein, mRNA, and heterogenous nuclear RNA (hnRNA). Furthermore, studies with transgenic mice carrying theSLC5A65′-regulatory region showed that chronic alcohol feeding leads to a significant decrease in promoter activity. Studies with HK-2 cells chronically exposed to alcohol again showed a marked reduction in carrier-mediated biotin uptake, which was associated with a significant reduction in promoter activity of the humanSLC5A65′-regulatory region. These findings demonstrate for the first time that chronic ethanol feeding inhibits renal biotin transport and that this effect is, at least in part, being exerted at the transcriptional level.