溶质载体家族26成员6（PAT1）缺失会下调近端小管直部顶端的钠/氢交换体。
Slc26a6 (PAT1) deletion downregulates the apical Na+/H+ exchanger in the straight segment of the proximal tubule.
作者信息
Petrovic Snezana, Barone Sharon, Wang Zhaohui, McDonough Alicia A, Amlal Hassane, Soleimani Manoocher
机构信息
Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0585, USA.
出版信息
Am J Nephrol. 2008;28(2):330-8. doi: 10.1159/000111826. Epub 2007 Nov 29.
BACKGROUND/AIM: Slc26a6 (PAT1, CFEX) is a major chloride/base exchanger located on the apical membrane of the kidney proximal tubule. The purpose of the present study was to examine the effect of Slc26a6 deletion on the apical Na+/H+ exchanger 3 (NHE3) in the straight segment (S3) of the proximal tubule, which is the major site for the reabsorption of filtered chloride in the kidney.
METHODS
The proximal tubule S3 segment was perfused and the intracellular pH and apical Na+/H+ exchanger activity and expression were measured.
RESULTS
In the proximal tubule straight segments that were microperfused in vitro, baseline intracellular pH, measured by BCPCF-AM, was 7.10 +/- 0.02 in Slc26a6-/- and 7.33 +/- 0.02 in Slc26a6+/+ animals, a significant reduction in Slc26a6 mutant mice (p < 0.00001). The activity of the apical Na+/H+ exchanger was 0.49 +/- 0.02 pH units/min in Slc26a6+/+ and 0.26 +/- 0.03 pH units/min in Slc26a6-/- animals, a significant reduction in Slc26a6-/- mice (p < 0.0001). Formate-induced intracellular alkalinization, which is mediated via NHE3, was significantly blunted in Slc26a6-/- animals, with an alkalinization magnitude of 0.16 pH unit in Slc26a6-/- versus 0.37 in Slc26a6+/+ animals (p < 0.00001, n = 5 separate animals). Angiotensin II stimulation of NHE3 activity was intact in Slc26a6-/- animals. Buffering capacity was comparable in Slc26a6+/+ and Slc26a6-/- mice. Immunoblotting and immunofluorescent labeling demonstrated comparable NHE3 abundance and distribution in kidney proximal tubules of Slc26a6+/+ and Slc26a6-/- mice.
CONCLUSION
In conclusion, Slc26a6 deletion downregulates the apical Na+/H+ exchanger activity in the straight segment of the proximal tubule. The absence of a significant renal sodium loss in Slc26a6-null mice, despite NHE3 downregulation in the in vitro perfused tubules, points to possible activation of signaling pathways that can stimulate the apical Na+/H+ exchanger in vivo.
背景/目的：溶质载体家族26成员6（Slc26a6，又称PAT1、CFEX）是位于肾近端小管顶端膜上的一种主要的氯/碱基交换体。本研究旨在探讨Slc26a6基因缺失对近端小管直部（S3段）顶端钠/氢交换体3（NHE3）的影响，该部位是肾脏中重吸收滤过氯的主要部位。
方法
对近端小管S3段进行灌注，并测量细胞内pH值以及顶端钠/氢交换体的活性和表达。
结果
在体外微量灌注的近端小管直部中，用BCPCF-AM测量的基础细胞内pH值，Slc26a6基因敲除小鼠为7.10±0.02，Slc26a6基因野生型小鼠为7.33±0.02，Slc26a6基因敲除小鼠显著降低（p<0.00001）。顶端钠/氢交换体的活性在Slc26a6基因野生型小鼠中为0.49±0.02pH单位/分钟，在Slc26a6基因敲除小鼠中为0.26±0.03pH单位/分钟，Slc26a6基因敲除小鼠显著降低（p<0.0001）。由NHE3介导的甲酸盐诱导的细胞内碱化在Slc26a6基因敲除小鼠中显著减弱，Slc26a6基因敲除小鼠的碱化幅度为0.16pH单位，而Slc26a6基因野生型小鼠为0.37（p<0.00001，n=5只不同的动物）。血管紧张素II对NHE3活性的刺激在Slc26a6基因敲除小鼠中是完整的。缓冲能力在Slc26a6基因野生型和Slc26a6基因敲除小鼠中相当。免疫印迹和免疫荧光标记显示，Slc26a6基因野生型和Slc26a6基因敲除小鼠肾近端小管中NHE3的丰度和分布相当。
结论
总之，Slc26a6基因缺失下调了近端小管直部顶端钠/氢交换体的活性。尽管在体外灌注的小管中NHE3下调，但Slc26a6基因敲除小鼠没有明显的肾钠丢失，这表明可能存在能在体内刺激顶端钠/氢交换体的信号通路的激活。
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