Thangaraju Muthusamy, Ananth Sudha, Martin Pamela M, Roon Penny, Smith Sylvia B, Sterneck Esta, Prasad Puttur D, Ganapathy Vadivel
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912-2100, USA.
J Biol Chem. 2006 Sep 15;281(37):26769-73. doi: 10.1074/jbc.C600189200. Epub 2006 Jul 26.
slc5a8 and slc5a12 represent the high affinity and low affinity Na+/lactate co-transporters, respectively, in the kidney. Here we show that these transporters are expressed in the apical membrane of the proximal tubular cells in mouse kidney, indicating that these transporters are likely to mediate the first step in the renal reabsorption of lactate. Interestingly, the renal expression of both transporters is almost completely ablated in mice homozygous for the deletion of the transcription factor c/ebpdelta. This effect is tissue-specific since the expression of the transporters is not affected in non-renal tissues. The functional role of C/EBPdelta in the expression of SLC5A8 and SLC5A12 is demonstrable in HEK293 cells in reporter assays using gene-specific promoters. The ablation of the transporters in the kidney is accompanied by a marked increase in urinary excretion of lactate as well as a decrease in blood levels of lactate in c/ebpdelta-/- mice. These data provide evidence for an obligatory role for slc5a8 and slc5a12 in the renal absorption of lactate. In addition, we show that urinary excretion of urate is significantly elevated in c/ebpdelta-/- mice even though the expression of URAT1, the transporter responsible for the apical membrane uptake of urate in renal proximal tubule, is not altered. These data provide in vivo evidence for the functional coupling between lactate reabsorption and urate reabsorption in the kidney. Thus, the fortuitous double knock-out of slc5a8 and slc5a12 in kidney in c/ebpdelta-/- mice reveals the physiologic role of these transporters in the renal handling of lactate and urate.
溶质载体家族5成员8（SLC5A8）和溶质载体家族5成员12（SLC5A12）分别代表肾脏中高亲和力和低亲和力的钠/乳酸共转运体。在此我们表明，这些转运体在小鼠肾脏近端小管细胞的顶膜中表达，这表明这些转运体可能介导肾脏乳酸重吸收的第一步。有趣的是，在纯合缺失转录因子C/EBPδ的小鼠中，这两种转运体的肾脏表达几乎完全缺失。这种效应具有组织特异性，因为这些转运体的表达在非肾脏组织中不受影响。在使用基因特异性启动子的报告基因检测中，HEK293细胞中可证明C/EBPδ在SLC5A8和SLC5A12表达中的功能作用。C/EBPδ基因敲除小鼠肾脏中转运体的缺失伴随着乳酸尿排泄显著增加以及血液中乳酸水平降低。这些数据为SLC5A8和SLC5A12在肾脏乳酸吸收中的必要作用提供了证据。此外，我们表明，尽管负责肾脏近端小管顶膜尿酸摄取的转运体尿酸盐转运蛋白1（URAT1）的表达未改变，但C/EBPδ基因敲除小鼠的尿酸尿排泄显著升高。这些数据为肾脏中乳酸重吸收和尿酸重吸收之间的功能偶联提供了体内证据。因此，C/EBPδ基因敲除小鼠肾脏中SLC5A8和SLC5A12的偶然双敲除揭示了这些转运体在肾脏处理乳酸和尿酸中的生理作用。
