Pathogenesis of Idiopathic Uric Acid Nephrolithiasis and Renal Lipotoxicity

项目摘要 尿酸(UA)肾结石占美国肾结石的8%-10%。我们的团队已经 特发性尿失禁肾结石(IUAN)以前的几个明显特征：(1)主要 潜在的异常是过度酸性的尿液，这增加了尿酸沉淀的风险。(2)少尿 PH值是由于净酸排泄量(NAE)增加和氨氮(NH4+)减少共同作用的结果 排泄物。(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)肾脏脂肪堆积(脂肪变性)发生在人类，并与低NH4+/NAE有关， (2)动物模型中的脂肪变性与酸尿和NH4+排泄障碍有关，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 尿液pH是尿路结石形成的必要条件，但不充分，提示存在不明原因的结石。 UA结晶的促进剂或不存在抑制剂。我们假设存在三个缺陷 尿路结石：(1)肾脏脂肪变性，损害肾脏NH4+排泄，导致酸性尿液。 在任何给定的酸负荷下。(2)增加内源有机酸产量和NAE。(3)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。 该提案的目标1将通过关联肾脏脂肪来确定肾脏脂肪变性的功能后果。 尿酸碱含量与人体及泛发性和肾脏动物模型的关系 特定的脂肪毒性。目的2将评估逆转人类、动物和细胞的肾脏脂肪变性的结果。 文化体系。目标3将描述尿液的物理化学背景，说明其形成原因 使用经典的物理化学技术对IUAN患者的UA结石进行检测。这项提议奠定了基础 对于肾脂肪毒性的新概念，确定其在尿酸结石形成中的病理生理作用， 描述尿酸结石形成的尿液物理化学背景，以及 为改进尿酸肾结石的诊断和治疗开辟新的途径。

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.