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: 7653921
• 负责人: KHASHAYAR SAKHAEE
• 金额: $ 37.68万
• 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/7653921
• 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; public health relevance; 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）肾结石占美国肾结石的8-10%。我们的研究小组先前已经描述了特发性UA肾结石（IUAN）的几个明显特征：（1）主要的潜在异常是过度酸性尿，这增加了UA沉淀的风险。(2)尿液pH值低是由于净酸排泄（NAE）增加和铵（NH 4+）排泄减少的综合作用。(3)患有2型糖尿病和/或肥胖的患者患IUAN的风险增加。我们的初步数据表明，（1）肾脏脂肪堆积（2）动物模型中的脂肪变性与酸尿和受损的NH 4+排泄（IUAN的特征）有关，（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，（4）低尿pH值是尿酸结石形成的必要条件，但不足以形成尿酸结石，提示尿酸结晶存在未知的促进剂或不存在抑制剂。我们假设UA结石患者存在三种缺陷：（1）肾脏脂肪变性，损害肾脏NH 4+排泄，导致任何给定酸负荷下的酸性尿。(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/或促进剂的存在可能另外导致UA结晶。本提案的目的1将通过在人类受试者和全身性和肾脏特异性脂毒性动物模型中将肾脏脂肪含量与尿酸碱参数相关联来确定肾脏脂肪变性的功能后果。目的2将评估逆转人类、动物和细胞培养系统中的肾脏脂肪变性的结果。目的3将使用经典的理化技术来描述IUAN患者UA结石形成的尿液理化背景。该建议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尿液理化背景，并为改善尿酸肾结石的诊断和治疗开辟了新途径。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平行增加。该提案为肾脏脂毒性（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，并表征了导致尿酸结石形成的尿液理化背景，为改善尿酸肾结石的诊断和治疗开辟了新途径。