Endothelial Dysfunction in the Pathogenesis of Sickle Cell Nephropathy

镰状细胞肾病发病机制中的内皮功能障碍

• 批准号: 8403679
• 负责人: DAVID R ARCHER
• 金额: $ 43.89万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403679
• 关键词: Address; Albumins; Albuminuria; Attenuated; Brain; Chronic Kidney Failure; Clinical; Creatinine; Data; Development; Disease; Echocardiography; Endothelial Cells; Excretory function; Exhibits; Family; Filtration; Functional disorder; Hemolysis; High Prevalence; Ischemic Stroke; Kidney; Kidney Diseases; Kidney Failure; Lead; Lung; Measures; Microalbuminuria; Mus; Organ; Pathogenesis; Patients; Plasma; Play; Pre-Eclampsia; Priapism; Process; Proteinuria; Pulmonary Hypertension; Regulation; Renal function; Reporting; Role; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Spleen; Testing; Transgenic Organisms; Ultrasonography; Up-Regulation; Urine; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vasodilation; Work; abstracting; atorvastatin; base; brachial artery; defined contribution; effective therapy; improved; macroalbuminuria; member; monocyte; mortality; penis; receptor; vascular bed

Abstract Although it is recognized that sickle cell disease (SCD) is characterized by the presence of endothelial dysfunction, the contribution of endothelial dysfunction to disease pathophysiology remains poorly defined. We, and others, have previously reported on an association of pulmonary hypertension and nephropathy in patients with SCD, suggesting that they may share a similar pathophysiology. More recently, we have found that SCD patients with macroalbuminuria (urine albumin excretion > 300 mg/g creatinine) have significantly elevated levels of both soluble vascular cell adhesion molecule-1 (VCAM-1), a measure of endothelial activation, and soluble fms-like tyrosine kinase-1 (sFLT-1), a member of the VEGF receptor family. sFLT-1 is known to induce endothelial dysfunction by sequestration of VEGF in plasma and/or by the formation of inactive receptors and reduced signal transduction. In addition, we found that sFLT-1 was significantly correlated with soluble VCAM-1 in SCD patients. This data, combined with the association of sFLT-1 with proteinuria in other disease states (such as preeclampsia) suggests that by inducing endothelial dysfunction, sFLT-1 may play an important role in the development of albuminuria in SCD. In the current application, we will define the contribution of endothelial dysfunction as well as the sFLT-1/VEGF axis to the pathogenesis of albuminuria in SCD patients and transgenic sickle cell mice. Furthermore, we will evaluate the effect of atorvastatin, an agent that is known to attenuate endothelial dysfunction and decrease sFLT-1 release, on endothelial dysfunction and albuminuria. With the limited therapies available for the treatment of SCD-related nephropathy, the demonstration of a role for endothelial dysfunction in the pathogenesis of albuminuria will facilitate the development of more effective treatments.

摘要 尽管认识到镰状细胞病（SCD）的特征在于存在 内皮功能障碍，内皮功能障碍对疾病病理生理学的贡献 仍然定义不清。我们和其他人以前曾报道过 SCD患者的肺动脉高压和肾病，这表明他们可能分享 相似的病理生理学最近，我们发现患有SCD的患者 大量白蛋白尿（尿白蛋白排泄> 300 mg/g肌酐）显著升高 可溶性血管细胞粘附分子-1（VCAM-1）水平， 激活，和可溶性fms样酪氨酸激酶-1（sFLT-1），VEGF受体的成员 家人已知sFLT-1通过在血浆中隔离VEGF而诱导内皮功能障碍 和/或通过形成无活性受体和减少的信号转导。另外我们 发现SCD患者sFLT-1与可溶性VCAM-1显著相关。这些数据， 结合sFLT-1与其他疾病状态（如糖尿病）中蛋白尿的相关性， 先兆子痫）提示sFLT-1通过诱导内皮功能障碍， 在SCD中蛋白尿的发展中的作用。 在本申请中，我们将定义内皮功能障碍的贡献以及内皮细胞的功能。 sFLT-1/VEGF轴在SCD患者蛋白尿发病中的作用及转基因镰状细胞 小鼠此外，我们将评估阿托伐他汀的作用，阿托伐他汀是一种已知的药物， 减轻内皮功能障碍并减少sFLT-1释放， 蛋白尿由于可用于治疗SCD相关肾病的疗法有限， 内皮功能障碍在蛋白尿发病机制中的作用的证明将 有助于开发更有效的治疗方法。