MITOCHONDRIAL FUNCTION IN RENAL STONE DISEASE

目前对草酸钙结石形成的研究主要涉及 有利于肾小管内草酸钙结晶的代谢紊乱。 然而，在管腔内形成的晶体不太可能达到 堵塞收集管道并形成微石所需的尺寸 在尿液从肾小球转运到肾小球 肾盆。因此，腔内游离晶体应该通过 自发地通过膀胱的收集系统。 关于肾结石发病机制的另一种假说是 初始晶体形成的位置在细胞内。线粒体具有 运输钙和磷的能力很强。中的更改 线粒体钙转运可见于肾钙质沉着症，而且是早期的 不同急性肾损伤模型肾细胞损伤指标的研究 失败了。此外，实验性肾结石几乎总是 伴随着线粒体形态的变化。目前还不清楚， 然而，如果线粒体草酸转运的改变出现在 肾结石或即使肾皮质线粒体可以转运 草酸盐。 在初步实验中，我们展示了肾皮质线粒体 在一个明显的浓度梯度下积累草酸。在一个 饲喂诱发草酸钙肾结石的实验模型 大鼠草酸铵对通电引起的跨膜草酸盐通量的影响 线粒体明显先于线粒体肿胀和管内 结晶。当肾小管功能障碍的大鼠喂饲铵时 草酸，草酸盐助熔剂的变化被夸大，胞内结晶 在草酸盐水平上检测到的形成是无害的 无肾小管功能障碍。 这项建议的目的是评估线粒体的作用 肾功能障碍在肾结石发病中的作用我们将研究，在 特别是线粒体草酸和钙处理的改变和 这些与细胞形态和近端小管的变化有关 功能。

Current research on calcium oxalate stone formation has primarily involved metabolic disorders favoring intratubular calcium oxalate crystallization. However, crystals formed within the tubular lumen are not likely to attain the dimensions required to block a collecting duct and form a microlith during the time it takes for urine to be transported from the glomerulus to the renal pelvis. Therefore, free intraluminal crystals should pass spontaneously through the collecting system of the bladder. An alternate hypothesis for the pathogenesis of renal stones is that the site of initial crystal formation is within the cell. Metochondria possess a great capacity to transport calcium and phosphate. Alterations in mitochondrial calcium transport are seen in nephrocalcinosis and are early indicators of renal cellular injury in a variety of models of acute renal failure. Furthermore, experimental nephrolithiasis is almost invariably accompanied in changes by mitochondrial morphology. It is not known, however, if an alteration in mitochondrial oxalate transport is present in nephrolithiasis or even if renal cortical mitochondria can transport oxalate. In preliminary experiments, we have shown the renal cortical mitochondria accumulated oxalate against an apparent concentration gradient. In an experimental model of calcium oxalate nephrolithiasis induced by feeding rats ammonium oxalate, a change in transmembrane oxalate flux by energized mitochondria clearly preceded mitochondrial swelling and intratubular crystallization. When rats with tubular dysfunction were fed ammonium oxalate, changes in oxalate flux were exaggerated and intracellular crystal formation was detected at levels of oxalate that were innocuous in the absence of tubular dysfunction. The objective of this proposal is to evaluate the role of mitochondrial dysfunction in the pathogenesis of nephrolithiasis. We will examine, in particular, alterations of mitochondrial oxalate and calcium handling and relate these to changes in cellular morphology and proximal tubular function.