PATHOPHYSIOLOGY AND MOLECULAR GENETIC BASIS OF GOUTY DIATHESIS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 本课题的总体目标是阐明痛风素质和尿酸性肾结石的病理生理基础。 痛风素质是一个描述性术语，适用于以尿酸肾结石、不同程度的肾脏尿酸潴留和血脂异常为特征的综合征。 尿液中的尿酸沉淀继发于酸性尿液pH，这使得尿酸不溶，但酸性尿液pH的原因尚不清楚。 我们已经表明，酸性尿pH值是次要的缺陷，尿铵排泄的主要尿缓冲。 此外，尿铵减少可能与外周胰岛素抵抗的程度相关。 研究假设： 肾脏胰岛素抵抗的一个表现是氨排泄受损。 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继发于与胰岛素抵抗相关的游离脂肪酸水平升高。 尽管减少的铵排泄不足以扰乱酸碱平衡，但足以降低尿pH并引起尿酸沉淀。 这种“肾胰岛素抵抗”是痛风素质综合征的一部分，并直接导致尿酸沉淀。

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.