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: 8818384
• 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/8818384
• 关键词: 2,4-thiazolidinedione; 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; public health relevance; randomized placebo controlled trial; saturated fat; single photon emission computed tomography; stem; uptake; urinary; volunteer

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(申请人提供)：肥胖和代谢综合征已经达到流行的比例，尿酸结石是这些人常见的卫生保健问题。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/代谢综合征和尿酸结石之间的流行病学联系是无可辩驳的，但其病理生理联系一直难以捉摸。尿酸沉淀最重要的一个因素是尿液pH值过低。我们已经证明，这源于利用氨缓冲质子的固有肾脏缺陷，无缓冲质子自由滴定尿酸为不溶性尿酸，并启动级联成石。我们建议使用细胞培养、动物和人类研究相结合的方法，利用磁共振光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检验四个相互关联的假说。1.肾脏对游离脂肪酸的摄取增加，这是由于循环水平较高以及近端小管优先转运的结果，这是“条件反射”效应的一部分。2.游离脂肪酸的增加为ATP的生成提供了代谢底物，从而减少了对谷氨酰胺等其他底物的消耗，谷氨酰胺是近端小管氨化作用的主要来源。这种底物竞争，或代谢开关，可以降低主要尿液缓冲氨的形成，即使在没有损伤近端小管的情况下也是如此。3.随着近端小管持续的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的脂毒性，表现为内质网(ER)泄漏/应激，我们认为氨化缺陷是更广泛的脂毒表型的一部分。我们进一步认为，一种特定的脂质物种的积累可能是毒性的原因。4.为了测试人类近端小管脂肪变性和脂肪毒性是否具有功能性后果，我们将研究尿酸结石形成物。在先前证明了噻唑烷二酮(TZD)可以减少动物的肾脏脂肪变性和脂肪毒性以及改善铵的排泄之后，我们启动了一项在人类尿酸结石患者中使用TZD或安慰剂的随机干预试验。中期分析显示，TZD治疗6个月后，结石患者的尿生化指标有所改善，尿酸沉着倾向降低。我们将继续这项试验，但增加一种新的高度敏感的方法来非侵入性地测量肾脏脂肪，测试尿液生化的改善是否与肾脏脂肪的减少有关。这项建议解决了肾小管脂质生物学和脂毒性的基本概念，并将在临床上将尿酸结石治疗的范式从经验性尿碱化转变为特异性的肾脂肪减少。我们还将介绍用于肾脏研究的尖端人体成像研究。