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: 8926954
• 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/8926954
• 关键词: Acidity; Acute; Address; Aftercare; Alkalinization; Ammonia; Ammonium; Animal Model; Animals; Automobile Driving; Biochemical; Biochemistry; Biology; Buffers; Calculi; 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程度，尿酸结石是这些人中常见的医疗保健问题。尿酸结石的发病率和患病率随着时间的推移而不断上升，给生活质量和医疗费用带来了巨大的负担。虽然肥胖/代谢综合征与尿酸结石之间的流行病学联系是无可辩驳的，但病理生理学联系却一直难以捉摸。导致尿酸沉淀的最重要因素是尿液 pH 值过低。我们已经证明，这源于利用氨缓冲质子的内在肾脏缺陷，未缓冲的质子可以自由地将尿酸盐滴定为不溶性尿酸并引发成岩级联。我们建议结合细胞培养、动物和人类研究，采用磁共振波谱和单光子发射计算机断层扫描的一些最新技术，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近端小管的优先运输（作为“调节”作用的一部分），肾脏对游离脂肪酸的吸收增加。 2.游离脂肪酸供应的增加为ATP生成提供了代谢底物，从而减少了其他底物的消耗，例如谷氨酰胺，谷氨酰胺是近端小管氨生成的主要来源。即使在近端小管没有损伤的情况下，这种底物竞争或代谢转换也可以降低主要尿液缓冲氨的形成。 3. 随着近端小管的持续脂质负荷超过其氧化能力，脂质储存首先被激活，但随着时间的推移，有毒的脂质代谢物可能会积聚。我们有证据表明，西方饮食中普遍存在的过量饱和脂肪会导致近端小管脂毒性，表现为内质网（ER）渗漏/应激，并且我们认为氨生成缺陷是更广泛的脂毒性表型的一部分。我们进一步提出，特定脂质种类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，我们将研究尿酸结石形成者。先前已证明噻唑烷二酮类 (TZD) 可减少动物的肾脂肪变性和脂毒性并改善铵排泄，因此我们启动了一项使用 TZD 或安慰剂治疗人类尿酸结石形成者的随机干预试验。中期分析显示，经过 6 个月的 TZD 治疗，结石形成者改善了尿生化参数并降低了尿酸沉淀的倾向。我们将继续这项试验，但增加一种新颖的高灵敏度方法来非侵入性测量肾脂肪，测试尿液生化的改善是否与肾脂肪的减少相关。该提案解决了肾小管脂质生物学和脂毒性的基本概念，并且在临床上将尿酸结石治疗的范式从经验性尿液碱化转变为特异性减少肾脂肪。我们还将介绍用于肾脏研究的尖端人体成像研究。