Pathogenesis of Uric Acid Nephrolithiasis: The Multifaceted Role of Renal Lipids

尿酸性肾结石的发病机制：肾脂质的多方面作用

• 批准号: 9103087
• 负责人: Orson W Moe
• 金额: $ 35.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103087
• 关键词: Acidity; Acute; Address; Aftercare; Alkalinization; Ammonia; Ammonium; Animal Model; Animals; Automobile Driving; Biochemical; Biochemistry; Biology; Buffers; Cell Culture Techniques; Consumption; Cultured Cells; Data; Defect; Diet; Disease; Double-Blind Method; Endoplasmic Reticulum; Epidemic; Epidemiology; Excretory function; Extravasation; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Funding; Future; Generations; Glutamine; Health; Health Care Costs; Healthcare; Healthcare Systems; Human; Hypertriglyceridemia; Image; Incidence; Individual; Injury; Intervention; Intervention Trial; Kidney; Kidney Calculi; Link; Lipids; Lysophosphatidylcholines; Magnetic Resonance Spectroscopy; Measurable; Measurement; Measures; Mediating; Metabolic; Metabolic syndrome; Methods; Mitochondria; Modeling; Molecular Biology; Mus; Nephrolithiasis; Nonesterified Fatty Acids; Obesity; Operative Surgical Procedures; Oral; Overweight; Participant; Pathogenesis; Patients; Phenotype; Physiology; Pioglitazone; Placebos; Precipitation; Prevalence; Production; Protons; Publishing; Quality of life; Randomized; Randomized Controlled Trials; Rattus; Research; Resolution; Risk; Role; Sampling; Serum; Source; Specimen; Stress; Techniques; Technology; Testing; Thiazolidinediones; Time; Tissues; Toxic effect; Triglycerides; Tubular formation; Up-Regulation; Urate; Uric Acid; Urine; X-Ray Computed Tomography; base; conditioning; cost; improved; in vivo; lipid metabolism; novel; randomized placebo controlled trial; saturated fat; single photon emission computed tomography; stem; uptake; urinary; volunteer; western diet

DESCRIPTION (provided by applicant): Obesity and the metabolic syndrome have reached epidemic proportions and uric acid stones are a common health care problem in these individuals. The incidence and prevalence of uric acid stones are escalating with time, imparting a significant burden on quality of life and health care cost. While the epidemiologic link between obesity / metabolic syndrome and uric acid stones is irrefutable, the pathophysiologic link has been elusive. The single most important factor driving uric acid precipitation is unduly low urine pH. We have shown that this stems from an intrinsic renal defect in the utilization of ammonia to buffer protons, with unbuffered protons free to titrate urate to insoluble uric acid and initiate te cascade of lithogenesis. We propose to use a combination of cell culture, animal, and human studies employing some of the latest technologies in magnetic resonance spectroscopy and single-photon emission computed tomography, combined with classical physiology, biochemistry, and molecular biology to test four interrelated hypotheses. 1. There is increased uptake of free fatty acids into the kidney as a result of higher circulating levels as well as preferential transport by the proximal tubule as part of a "conditioning" effect. 2. The increased provision of free fatty acid supplies metabolic substrate for ATP generation hence reducing the consumption of other substrates such as glutamine, which is the principal source of ammoniagenesis by the proximal tubule. This substrate competition, or metabolic switch, can lower the formation of the major urinary buffer ammonia, even in the absence of injury to the proximal tubule. 3. With sustained lipid loading of the proximal tubule that exceeds its oxidative capacity, lipid storage is first activated but with time, toxic lipid metabolites may build up. We have evidence that excess saturated fat, which is prevalent in the Western diet, leads to proximal tubule lipotoxicity manifested as endoplasmic reticulum (ER) leakage/stress, and we propose that defective ammoniagenesis is part of a broader lipotoxic phenotype. We further propose that accumulation of a specific lipid species may be responsible for the toxicity. 4. To test whether proximal tubule steatosis and lipotoxicity in humans have a functional consequence, we will study uric acid stone formers. Having previously shown that thiazolidinediones (TZD) reduce renal steatosis and lipotoxicity and improve ammonium excretion in animals, we have initiated a randomized intervention trial with TZD or placebo in human uric acid stone formers. The interim analysis showed that after 6 months of TZD therapy, stone formers had improved urinary biochemical parameters and reduced propensity for uric acid precipitation. We will continue this trial but add a novel highly sensitive method to non-invasively measure renal fat, testing whether improvement in urinary biochemistry associates with reduction of renal fat. This proposal addresses fundamental concepts of renal tubular lipid biology and lipotoxicity, and clinically will shift the paradigm of uric acid stone therapy from empiric urinary alkalinization to specific reduction in renal fat. We will also introduce cutting-edge human imaging studies for kidney research.

描述（由申请人提供）：肥胖和代谢综合征已达到流行比例，而尿酸结石是这些人的常见医疗保健问题。尿酸结石的发病率和流行率随着时间的推移而升级，给生活质量和医疗保健成本带来了重大负担。尽管肥胖 /代谢综合征与尿酸结石之间的流行病学联系是无法理解的，但病理生理联系仍然难以捉摸。驱动尿酸沉淀的单一最重要的因素是过度低尿液pH。我们已经表明，这源于氨使用对缓冲质质子的固有肾脏缺陷，没有无封闭的质子可以滴定尿酸盐以滴定至不溶性尿酸，并启动了岩性生成的TE级联。我们建议将细胞培养，动物和人类研究结合使用，这些细胞培养，动物和人类研究采用磁共振光谱和单光子发射计算机断层扫描中的一些最新技术，并结合经典生理学，生物化学和分子生物学来测试四个相互关联的假设。 1。由于较高的循环水平以及通过近端小管的优先运输，自由脂肪酸的吸收增加了，这是“调节”效应的一部分。 2。自由脂肪酸提供的增加提供了代谢基质，以减少其他底物的消耗，例如谷氨酰胺，谷氨酰胺是近端小管的主要氨基酸性来源。即使在没有损伤的情况下，这种底物竞争或代谢开关也可以降低主要的尿缓冲氨的形成。 3。近端小管的持续脂质负荷超过其氧化能力，首先激活脂质储存，但随着时间的推移，有毒脂质代谢物可能会堆积。我们有证据表明，在西部饮食中普遍存在的饱和脂肪过多，导致近端小管脂毒性表现为内质网（ER）泄漏/应力，我们建议有缺陷的氨基毒素发生是较广泛的脂毒性表型的一部分。我们进一步建议，特定脂质物种的积累可能是造成毒性的原因。 4。为了测试人类近端小管脂肪变性和脂毒性是否具有功能性后果，我们将研究尿酸石材形成器。先前表明噻唑烷二酮（TZD）降低了肾脏脂肪变性和脂肪毒性，并改善了动物的铵排泄，我们已经在人类尿酸石材中对TZD或安慰剂进行了随机干预试验。临时分析表明，经过6个月的TZD治疗后，石材成型器改善了尿生化参数，尿酸沉淀倾向降低。我们将继续这项试验，但添加了一种新型的高度敏感方法来非侵入性测量肾脏脂肪，从而测试肾脏脂肪减少的尿生物化学联合的改善。该建议介绍了肾小管脂质生物学和脂毒性的基本概念，并且在临床上将将尿酸石疗法的范式从经验性尿碱化转变为肾脏脂肪的特定降低。我们还将引入肾脏研究的尖端人类影像学研究。