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: 8072745
• 负责人: KHASHAYAR SAKHAEE
• 金额: $ 33.47万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072745
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Uric acid stone disease is strongly associated with obesity and type 2 diabetes, and its prevalence may increase in parallel with the obesity epidemic. This proposal lays the foundation for the novel concept of renal lipotoxicity (fat accumulation within the kidney), identify its pathophysiologic role in uric acid stone formation, and 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.

描述（由申请人提供）：尿酸（UA）肾结石在美国占肾结石的8-10%。我们的研究小组先前描述了特发性UA肾结石（IUAN）的几个不同特征：(1)主要的潜在异常是尿液过酸，这增加了UA沉淀的风险。(2)尿pH偏低是净酸排泄量（NAE）增加和铵（NH4+）排泄量减少共同作用的结果。(3) 2型糖尿病和/或肥胖患者发生IUAN的风险增加。我们的初步数据表明：(1)肾脏脂肪堆积（脂肪变性）发生在人类身上，并与低NH4+/NAE有关；(2)动物模型中的脂肪变性与酸尿和NH4+排泄受损有关，这是IUAN的特征；(3)细胞培养模型中的脂肪变性导致脂肪毒性，表现为NH4+分泌减少；(4)低尿pH值是UA结石形成的必要条件，但不是充分条件。这表明存在未知的启动子或缺乏UA结晶的抑制剂。我们假设UA结石患者存在三个缺陷：(1)肾脏脂肪变性，损害肾脏NH4+排泄，导致任何给定酸负荷下的酸性尿液。(2)内源有机酸产量和NAE增加。(3)在IUAN患者中，尿路抑制剂的缺乏和/或启动子的存在可能是UA结晶的另一个原因。本提案的目的1将通过将肾脏脂肪含量与尿酸碱参数在人类受试者和广义和肾脏特异性脂肪毒性动物模型中的相关性来确定肾脂肪变性的功能后果。目的2将评估在人类、动物和细胞培养系统中逆转肾脂肪变性的结果。目的3将使用经典的物理化学技术描述IUAN患者UA结石形成的尿液物理化学背景。本研究为肾脂毒性的新概念奠定了基础，确定了其在尿酸结石形成中的病理生理作用，描述了尿酸结石形成的泌尿物理化学背景，为改善尿酸肾结石的诊断和治疗开辟了新的途径。公共卫生相关性：尿酸结石病与肥胖和2型糖尿病密切相关，其患病率可能与肥胖流行同步增加。本研究为肾脂毒性（肾脏内脂肪积聚）的新概念奠定了基础，确定了其在尿酸结石形成中的病理生理作用，并描述了尿酸结石形成的泌尿物理化学背景，为改善尿酸肾结石的诊断和治疗开辟了新的途径。