SNPs of metabolism, not stones.
SNPs of metabolism, not stones.
复制标题
新陈代谢的 SNP，而不是结石。
DOI：
10.1152/ajprenal.00432.2010
复制
发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Romero,MichaelF
中科院分区：
文献类型：
--
作者：
Romero,MichaelF
二羧酸是氧化磷酸化的底物，也就是克雷布斯循环或柠檬酸循环。这些底物中的一些在细胞内合成。然而，具有高代谢需求的上皮细胞（例如，小肠和肾脏）将这些底物直接带入细胞。细胞的质膜由于这种脂双层的疏水核心而将外部世界与内部分开。后一种性质意味着离子和溶质（用于代谢或其他）必须由转运蛋白携带通过环境。这些转运蛋白利用ATP水解或电化学梯度的能量来完成这一任务。Na偶联二羧酸协同转运蛋白（NaDC 1，SLC 13 A2）位于这些上皮细胞的顶膜（15，19），负责肾脏和肠道二羧酸以及柠檬酸（三羧酸）摄取。正如预期的那样，敲除小鼠中的NaDC 1会导致尿液柠檬酸盐和其他代谢物升高（7）。在平均70公斤的人体中，细胞代谢产生70 mmol的酸（H）。尿液缓冲液（如柠檬酸盐）也被称为可滴定酸，因为它们可以从代谢中吸收这种H。具有讽刺意味的是，这意味着H受体被认为是“碱基”。肾近端小管吸收70-90%的尿柠檬酸盐，其从过滤的血液进入肾单位。柠檬酸盐的近端小管代谢产生细胞内HCO 3，其可缓冲细胞内pH值或通过产电Na-HCO 3协同转运蛋白（NBCe 1-A）被吸收到血液中（4，8，18），导致跨上皮NaHCO 3吸收。酸中毒刺激HCO 3吸收，但也已知会增加NaDC 1 mRNA和蛋白质的量（2）以及NaDC 1活性（1，6）。由于柠檬酸盐代谢导致HCO 3产生并增加血液中HCO 3浓度，酸中毒导致尿柠檬酸盐减少（NaDC 1活性增加，超滤液中柠檬酸盐减少）。碱中毒通过减少基底外侧HCO 3排出（通过NBCe 1-A）减少经上皮HCO 3吸收。碱中毒导致近端超滤液的pH值升高，这种升高的管腔pH值降低了柠檬酸盐的吸收，并增加了尿液柠檬酸盐的排泄（3，9，11，20）。碱中毒（在负鼠肾细胞中）似乎确实降低了柠檬酸盐的NaDC 1共转运，但不降低琥珀酸盐的共转运（1）。这一观察似乎是一致的：当pH值超过6.4时，H-柠檬酸盐2浓度降低（首选二羧酸盐），而柠檬酸盐3浓度升高（三羧酸盐）（pKa 3 6.4; H-柠檬酸盐2-H柠檬酸盐3）。因此，这种pH值变化导致转运底物（H-柠檬酸盐2）减少。也就是说，近端小管通过限制柠檬酸盐吸收来响应，从而导致较高的尿柠檬酸盐（3，7）。
DICARBOXYLATES ARE THE SUBSTRATES for oxidative phosphorylation, aka the Krebs cycle or citric acid cycle. Some of these substrates are synthesized within cells. However, epithelia with high metabolic needs (eg, the small intestine and kidney) bring these substrates directly into cells. The plasma membrane of cells separates the outside world from the inside due to the hydrophobic core of this lipid bilayer. This latter property means that ions and solutes (for metabolism or otherwise) must be carried by a transporter protein through the environment. These transporters use either the energy of ATP hydrolysis or of the electrochemical gradient to accomplish this task. The Na-coupled dicarboxylate cotransporter (NaDC1, SLC13A2) is localized at the apical membrane of these epithelia (15, 19) and is responsible for renal and gut dicarboxylate as well as citrate (tricarboxylate) uptake. As expected, knocking out NaDC1 in mice causes elevated urinary citrate and other metabolites (7).In the average 70-kg human, cellular metabolism generates 70 mmol of acid (H). Urinary buffers such as citrate are also known as titratable acids because they can take on this H from metabolism. Ironically, this means that H acceptors are considered “bases.” The renal proximal tubule absorbs 70–90% of urinary citrate, which enters the nephron from the filtered blood. Proximal tubule metabolism of citrate results in intracellular HCO3, which either buffers intracellular pH or is absorbed into the blood via the electrogenic Na-HCO3 cotransporter (NBCe1-A)(4, 8, 18), leading to transepithelial NaHCO3 absorption. Acidosis stimulates HCO3 absorption but is also known to increase the amount of NaDC1 mRNA and protein (2) as well as NaDC1 activity (1, 6). Since citrate metabolism leads to HCO3 production and increases blood HCO3 concentration, acidosis decreases urinary citrate (increased NaDC1 activity¡ a decrease in citrate in the ultrafiltrate). Alkalosis reduces transepithelial HCO3 absorption by reducing basolateral HCO3 exit (via NBCe1-A). Alkalosis causes a pH increase of the proximal ultrafiltrate, and this elevated luminal pH decreases citrate absorption and enhances urinary citrate excretion (3, 9, 11, 20). Alkalosis (in opossum kidney cells) does seem to decrease NaDC1 cotransport of citrate but not succinate (1). This observation seems consistent: a decreasing H-citrate2 concentration (preferred dicarboxylate) and increasing citrate3 concentration (a tricarboxylate) as pH increases beyond 6.4 (pKa3 6.4; H-citrate2¡ H citrate3). This pH shift, thus results in less of the transported substrate (H-citrate2). That is, the proximal tubule responds by limiting citrate absorption, resulting in higher urinary citrate (3, 7).