RENAL BASIS OF HYPOCITRATURIA

肾结石的病因有哪些？肾结石的病因有哪些？柠檬酸盐在肾小球中自由过滤，尿柠檬酸盐排泄主要受近端小管中柠檬酸盐重吸收和代谢速率的调节。重吸收由NaDC-1基因编码的顶膜3 Na +/柠檬酸盐协同转运蛋白介导，代谢由两种途径之一介导：线粒体途径，介导三羧酸循环中的柠檬酸盐代谢;细胞质途径，ATP柠檬酸盐裂解酶将柠檬酸盐代谢为乙酰辅酶A和草酰乙酸。拟定的研究将检查负责调节柠檬酸盐重吸收和代谢的分子机制，重点是NaDC-1。目标1中的研究将阐明慢性代谢性酸中毒、K+缺乏、碱饲料和饥饿大鼠中NaDC-1调节的分子机制。目标2中的研究将进一步阐明NaDC-1在暴露于酸性细胞外液的培养近端小管细胞中调节的分子机制。这些研究将利用表达天然NaDC-1的细胞，以及表达稳定转染的标记NaDC-1和瞬时转染的报告基因构建体的细胞。目标1和2将共同解决NaDC-1的调控问题。目标3中的研究将解决已知由酸中毒激活的信号通路在NaDC-1调节中的作用。这些途径包括：1）酪氨酸激酶和MAP激酶途径; 2）糖皮质激素;和3）内皮素。目标4中的研究将使用13 C NMR光谱定量肾近端小管线粒体和细胞质途径中的柠檬酸盐代谢。最后，目标5中的研究将讨论高钾血症是否会导致高柠檬酸尿，从而导致高钾血症性肾远端肾小管酸中毒患者缺乏肾结石倾向。这些研究将使我们能够继续了解近端小管中肾脏柠檬酸盐处理的调节机制。

Description: (Taken directly from the application) Hypocitraturia is an important cause of kidney stones. Citrate is freely filtered in the glomerulus, and urinary citrate excretion is regulated principally by the rate of citrate reabsorption and metabolism in the proximal tubule. Reabsorption is mediated by an apical membrane 3Na+/citrate cotransporter encoded by the NaDC-1 gene, and metabolism is mediate by one of two pathways: a mitochondrial pathway that mediates citrate metabolism in the tricarboxylic acid cycle; and a cytoplasmic pathway in which ATP citrate lyase metabolizes citrate to acetyl CoA and oxaloacetate. The proposed studies will examine the molecular mechanisms responsible for regulation of citrate reabsorption and metabolism, focusing on NaDC-1. Studies in Aim 1 will address the molecular mechanisms of NaDC-1 regulation in rats with chronic metabolic acidosis, K+ deficiency, alkali feeding, and starvation. Studies in Aim 2 will further address the molecular mechanisms of NaDC-1 regulation in cultured proximal tubule cells exposed to acidic extracellular fluid. These studies will utilize cells expressing native NaDC-1, as well as cells expressing stably transfected tagged NaDC-1, and transiently transfected reporter constructs. Aim 1 and 2 together will address the regulation of NaDC-1. Studies in Aim 3 will address the role of signaling pathways known to be activated by acidosis in the regulation of NaDC-1. These pathways include: 1) tyrosine kinase and MAP kinase pathways; 2) glucocorticoids; and 3) endothelin. Studies in Aim 4 will quantitate citrate metabolism in mitochondrial and cytoplasmic pathways of the renal proximal tubule using 13C NMR spectroscopy. Lastly, studies in Aim 5 will address whether hyperkalemia causes hypercitraturia and thus is responsible for the lack of predisposition to nephrolithiasis in hyperkalemic renal distal tubular acidosis. These studies will allow us to continue to pursue an understanding of the mechanisms of regulation of renal citrate handling in the proximal tubule.