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

描述(申请人提供)：尿酸(UA)肾结石占美国肾结石的8-10%。我们小组以前已经描述了特发性尿酸肾结石(IUAN)的几个明显特征：(1)主要的潜在异常是过度酸性的尿液，这增加了尿酸沉淀的风险。(2)尿液pH低是净酸排泄量(NAE)增加和铵(NH4+)排出减少共同作用的结果。(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)人类肾脂肪堆积(脂肪变性)与低NH4+/NAE有关，(2)动物模型中的脂肪变性与酸尿和NH4+排泄障碍有关，IUAN的特征，(3)细胞培养模型中的脂肪变性导致脂毒性，表现为NH4+分泌减少，以及(4)低尿pH是UA结石形成所必需的，但不是充分的，这表明存在未知的促进剂或UA结晶抑制物的存在。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，导致在任何给定的酸负荷下出现酸性尿液。(2)增加内源有机酸产量和NAE。(3)在IUAN患者中，尿液抑制物的缺乏和/或启动子的存在可能是尿酸结晶的另一个原因。这项建议的目标1将通过将受试者的肾脏脂肪含量与尿酸碱参数以及泛发性和肾脏特异性脂毒性的动物模型相关联，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肾脏脂肪变性的结果。目的3将用经典的物理化学技术描述IUAN患者尿路结石形成的尿液物理化学背景。这一建议为肾脂肪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，表征了尿酸结石形成的尿液物理化学背景，并为改进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，其患病率可能会随着肥胖的流行而增加。这一建议为肾脂肪毒性(肾脏内脂肪堆积)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，并表征了尿酸结石形成的尿理化背景，为改进尿酸肾结石的诊断和治疗开辟了新的途径。

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.