Pathogenesis of Idiopathic Uric Acid Nephrolithiasis: The Role of Renal Lipotoxic

特发性尿酸性肾结石的发病机制：肾脂毒性的作用

• 批准号: 8457149
• 负责人: KHASHAYAR SAKHAEE
• 金额: $ 32.3万
• 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 2014-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457149
• 关键词: 2,4-thiazolidinedione; Accounting; Acids; Ammonium; Animal Model; Animals; Biochemical; Biochemistry; Buffers; Calculi; Cell Culture System; Cell Culture Techniques; Chemistry; Complex; Crystallization; Data; Defect; Deposition; Diagnosis; Disease; Epidemic; Excision; Excretory function; Fatty acid glycerol esters; Forms Controls; Foundations; Growth; Histologic; Human; Individual; Infiltration; Kidney; Kidney Calculi; Magnetic Resonance Spectroscopy; Measures; Metabolic syndrome; Modeling; Nephrectomy; Nephrolithiasis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Patients; Pioglitazone; Precipitation; Predisposition; Prevalence; Production; Publishing; Risk; Role; Solubility; Specimen; Techniques; Testing; Thiazolidinediones; United States; Urate; Uric Acid; Urine; advanced disease; base; human subject; improved; inhibitor/antagonist; novel; organic acid; promoter; urinary

Project Summary Uric Acid (UA) nephrolithiasis constitutes 8-10% of kidney stones in the United States. Our group has previously characterized several distinct features of idiopathic UA nephrolithiasis (IUAN): (1) The principal underlying abnormality is an unduly acidic urine which increases the risk of UA precipitation. (2) The low urine pH is due to the combined effect of increased net acid excretion (NAE) and reduced ammonium (NH4+) excretion. (3) Patients with type 2 diabetes and/or obesity are at increased risk for IUAN. Our preliminary data suggest that (1) renal fat accumulation (steatosis) occurs in humans, and is associated with low NH4+/NAE, (2) steatosis in an animal model is associated with aciduria and impaired NH4+ excretion, features of IUAN, (3) steatosis in a cell culture model results in lipotoxicity which manifests as reduced NH4+ secretion, and (4) low urinary pH is necessary but not sufficient for UA stone formation, suggesting the presence of unknown promoters or the absence of inhibitors of UA crystallization. We hypothesize that three defects are present in UA stone formers: (1) Steatosis of the kidney which impairs renal NH4+ excretion, resulting in an acidic urine at any given acid load. (2) Increased endogenous organic acid production and NAE. (3) In IUAN patients, the lack of a urinary inhibitor and/or the presence of a promoter may additionally account for UA crystallization. Aim 1 of this proposal will determine the functional consequences of renal steatosis by correlating kidney fat content with urinary acid-base parameters in human subjects and in animal models of generalized and kidney- specific lipotoxicity. Aim 2 will evaluate the outcome of reversing renal steatosis in humans, animals, and cell culture systems. Aim 3 will characterize the urinary physicochemical background accounting for the formation of UA stones in IUAN patients using classical physicochemical techniques. This proposal lays the foundation for the novel concept of renal lipotoxicity, identify its pathophysiologic role in uric acid stone formation, characterize the urinary physicochemical background accounting for the formation of uric acid stones, and open new avenues for improved diagnosis and treatment of uric acid nephrolithiasis.

项目摘要 尿酸（UA）肾结石占美国肾结石的8-10%。我们集团 特发性UA肾结石（IUAN）的几个明显特征：（1）主要的 潜在的异常是过度酸性的尿液，这增加了UA沉淀的风险。(2)低尿 pH值是由于净酸排泄量（NAE）增加和铵（NH 4+）减少的综合作用所致。 排泄(3)患有2型糖尿病和/或肥胖的患者患IUAN的风险增加。我们的初步数据 提示（1）肾脏脂肪蓄积（脂肪变性）发生在人体中，并与低NH 4 +/NAE相关， (2)动物模型中脂肪变性与酸尿和NH 4+排泄受损相关，这是IUAN的特征，（3） 细胞培养模型中的脂肪变性导致脂毒性，其表现为减少的NH 4+分泌，和（4）低 尿pH值是UA结石形成所必需的，但不足以形成UA结石，这表明存在未知的 促进剂或不存在UA结晶的抑制剂。我们假设存在三个缺陷， UA结石形成者：（1）肾脏脂肪变性，损害肾脏NH 4+排泄，导致酸性尿 在任何给定的酸负荷下。(2)增加内源性有机酸的产生和NAE。(3)在IUAN患者中， 尿抑制剂的缺乏和/或促进剂的存在可另外解释UA结晶。 本提案的目的1将通过将肾脏脂肪与肾脏脂肪变性的相关性来确定肾脏脂肪变性的功能后果。 内容与尿酸碱参数在人类受试者和动物模型的广义和肾- 特异性脂毒性。目的2将评估逆转人、动物和细胞中肾脏脂肪变性的结果。 文化体系。目的3将描述尿理化背景的形成， 使用经典的理化技术对IUAN患者的UA结石进行分析。这一建议奠定了基础， 对于肾脂毒性的新概念，确定其在尿酸结石形成中的病理生理作用， 表征导致尿酸结石形成的尿液理化背景，以及 为提高尿酸性肾结石的诊断和治疗开辟了新的途径。