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: 7812212
• 负责人: KHASHAYAR SAKHAEE
• 金额: $ 37.3万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812212
• 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）肾石器症占美国肾结石的8-10％。我们的小组先前已经表征了特发性UA肾石岩症（IUAN）的几个不同特征：（1）主要的基本异常是一种过度酸性的尿液，它增加了UA沉淀的风险。 （2）低尿液pH是由于净酸排泄增加（NAE）和降低铵（NH4+）排泄的综合作用。 （3）2型糖尿病和/或肥胖症患者的IUAN风险增加。我们的初步数据表明，（1）肾脏脂肪的积累（脂肪变性）发生在人类中，并且与低Nh4+/nae相关，（2）动物模型中的脂肪变性与酸尿和NH4+排泄，IUAN的特征（3）在细胞培养模型中的特征在脂肪毒性中降低了lipotoxic section nh nhh nh4+ nh4+的特征，这是lipotoxic section nh nh nh nh nh nh nh nh use nh的特征。但不足以形成UA，表明存在未知的启动子或不存在UA结晶的抑制剂。我们假设在UA石材的形成器中存在三个缺陷：（1）肾脏会损害肾脏NH4+排泄，导致在任何给定的酸负荷下酸性尿液。 （2）增加内源性有机酸的产生和NAE。 （3）在IUAN患者中，缺乏尿液抑制剂和/或启动子的存在可能还可以解释UA结晶。该提案的目标1将通过将肾脏脂肪含量与人类受试者中的尿酸基碱参数以及广义和肾脏特异性脂肪毒性的动物模型相关联，来确定肾脂肪变性的功能后果。 AIM 2将评估逆转人类，动物和细胞培养系统中肾脏脂肪变性的结果。 AIM 3将表征使用经典理化技术在IUAN患者中形成UA石头的尿理化背景。该提案为肾脂毒性的新颖概念奠定了基础，确定了其在尿酸结石形成中的病理生理作用，表征了尿液化学背景，占尿酸石的形成，并开放了新的途径，以改善尿酸肾硫代症的诊断和治疗。公共卫生相关性：尿酸石材疾病与肥胖症和2型糖尿病密切相关，其患病率可能与肥胖症流行同时增加。该提议为肾脂肪毒性的新颖概念（肾脏内的脂肪积累）奠定了基础，确定其在尿酸结石形成中的病理生理作用，并表征了尿液化学背景，以说明形成尿酸石的形成，并开放新的途径，以改善和治疗尿酸酸性肾上腺素的诊断和处理。