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 堵塞集水管和形成微石所需的尺寸 在尿液从肾小球转运到 肾盂 因此，游离的腔内晶体应通过 自发地通过膀胱的收集系统。 肾结石的发病机制的另一种假设是， 最初晶体形成的位置在细胞内。 梅托拉拥有 有很强的钙和磷酸盐运输能力 的改变 线粒体钙转运见于肾钙质沉着症， 各种急性肾损伤模型中肾细胞损伤的指标 失败 此外，实验性肾结石几乎总是 伴随着线粒体形态的改变。 不知道， 然而，如果线粒体草酸盐转运的改变存在于 肾结石或甚至肾皮质线粒体可以运输 草酸盐。 在初步实验中，我们已经显示了肾皮质线粒体 积累的草酸盐对表观浓度梯度。 中 进食诱发草酸钙肾结石实验模型 大鼠草酸铵，改变跨膜草酸通量的通电 线粒体明显先于线粒体肿胀， 晶化 当肾小管功能障碍的大鼠被喂食氨 草酸，草酸通量的变化被夸大，细胞内晶体 在无害的草酸水平下检测到形成， 没有肾小管功能障碍。 这项建议的目的是评估线粒体的作用， 肾结石发病机制中的功能障碍。 我们将研究，在 特别是，线粒体草酸盐和钙处理的改变， 这些与细胞形态学和近端肾小管的变化有关， 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.