PATHOPHYSIOLOGY AND MOLECULAR GENETIC BASIS OF GOUTY DIATHESIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。本项目的总体目标是阐明痛风素质和尿酸肾结石的病理生理学基础。痛风素质是一个描述性术语，用于描述以尿酸肾结石、不同程度的尿酸滞留和血脂异常为特征的综合征。尿液中尿酸的沉淀次于酸性尿液的pH值，这使得尿酸不能溶解，但导致酸性尿液pH值的原因尚不清楚。我们已经证明，酸性尿液pH值是次要的尿氨排泄缺陷，尿液的主要缓冲。此外，尿氨降低可与外周胰岛素抵抗的程度相关。研究假设：肾脏中胰岛素抵抗的一个表现是铵排泄障碍。尿铵排泄的减少可能是由于胰岛素对肾脏本身的作用减少，或者继而是与胰岛素抵抗相关的游离脂肪酸水平升高所致。虽然减少的铵排泄不足以扰乱酸碱平衡，但足以降低尿液pH值并引起尿酸沉淀。这种“肾脏胰岛素抵抗”是痛风素质综合症的一部分，直接导致尿酸沉淀。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this project is to elucidate pathophysiologic basis of gouty diathesis and uric acid nephrolithiasis. Gouty diathesis is a descriptive term applied to a syndrome characterized by uric acid nephrolithiasis, varying degrees of renal uric acid retention, and dyslipidemia. Uric acid precipitation in the urine is secondary to acidic urine pH, which renders the uric acid insoluble but the cause of the acidic urine pH is unknown. We have shown that the acidic urine pH is secondary to defects in urinary ammonium excretion' the major urinary buffer. Furthermore, the reduced urinary ammonium can be correlated with the degree of peripheral insulin resistance. The study hypothesis: That a manifestation of insulin resistance in the kidney is impaired ammonium excretion. The reduction of urinary ammonium excretion can be due to decreased insulin action on the kidney per se or secondary to the elevated free fatty acid levels associated with insulin resistance. although the reduced ammonium excretion is insufficient to disturb acid-base balance, it is sufficient to lower urinary pH and cause uric acid precipitation. This "renal insulin resistance" is part of the syndrome of gouty diathesis and contributes directly to uric acid precipitation.