PATHOPHYSIOLOGY AND MOLECULAR GENETIC BASIS OF GOUTY DIATHESIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究旨在探讨痛风及尿酸性肾结石的病理生理基础。痛风素质是一种描述性术语，适用于以尿酸肾结石、不同程度的肾尿酸潴留和血脂异常为特征的综合征。尿液中的尿酸沉淀是继发于酸性尿pH，这使得尿酸不溶，但酸性尿pH的原因尚不清楚。我们已经表明，酸性尿液pH值是继发于尿铵排泄缺陷（尿铵是主要的尿缓冲液）。此外，尿铵的减少与外周胰岛素抵抗的程度有关。本研究假设：肾脏胰岛素抵抗的一个表现是氨的排泄受损。尿铵排泄量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。虽然减少的铵排泄不足以扰乱酸碱平衡，但足以降低尿pH值，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.