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

基本信息

批准号：
8221131
负责人：
DAVID R ARCHER
金额：
$ 50.46万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/8221131
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 atorvastatin base brachial artery defined contribution effective therapy improved macroalbuminuria member monocyte mortality penis receptor vascular bed

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The contribution of endothelial dysfunction to the pathophysiology of SCD remains poorly defined. However, patients with certain SCD-related complications such as albuminuria and pulmonary hypertension are known to exhibit evidence of endothelial dysfunction based on increased levels of soluble vascular cell adhesion molecule-1 (VCAM-1). Furthermore, these patients manifest evidence of increased levels of soluble fms-like tyrosine kinase-1 (sFLT-1), a member of the VEGF receptor family that is known to induce endothelial dysfunction. In this application, we will explore the contribution of endothelial dysfunction, as well as the sFLT-1/VEGF axis to the pathogenesis of albuminuria in SCD by addressing the following specific aims: We will evaluate the association of albuminuria with endothelial dysfunction, assessed non-invasively by ultrasound imaging of the brachial artery, in patients with sickle cell disease; we will test the hypothesis that in transgenic sickle cell mice, altered regulation of VEGF by sFLT-1 results in glomerular endothelial dysfunction and albuminuria; and finally, we will evaluate the effect of atorvastatin on endothelial dysfunction and albuminuria in patients with SCD.

描述（由申请人提供）：尽管人们认识到镰状细胞疾病（SCD）的特征是存在内皮功能障碍，但内皮功能障碍对疾病病理生理学的贡献仍然很差。我们和其他人先前已经报道了SCD患者肺动脉高压和肾病的关联，这表明他们可能具有类似的病理生理学。最近，我们发现患有大醛尿尿症（尿白蛋白排泄> 300 mg/g肌酐）的SCD患者在两个可溶性血管细胞粘附分子-1（VCAM-1）的水平显着升高，衡量了内皮活化的量度，内皮激活和可溶性FMS-FMS样酪氨酸基因酶-1（sflt-1）（sflt-1）（sflt-1）。已知SFLT-1通过在血浆中的VEGF和/或形成非活性受体并减少信号转导而诱导内皮功能障碍。此外，我们发现SFLT-1与SCD患者的可溶性VCAM-1显着相关。该数据与其他疾病状态中SFLT-1与蛋白尿的关联结合（例如先兆子痫）表明，通过诱导内皮功能障碍，SFLT-1可能在SCD中的蛋白尿发展中起重要作用。在当前的应用中，我们将定义内皮功能障碍以及SFLT-1/VEGF轴对SCD患者和转基因镰状细胞小鼠的蛋白尿发病机理的贡献。此外，我们将评估Atorvastatin的作用，Atorvastatin是一种众所周知的代理，可减弱内皮功能障碍并减少SFLT-1释放，对内皮功能障碍和蛋白尿。鉴于可用于治疗SCD相关肾病的有限疗法，在蛋白尿发病机理中，内皮功能障碍的作用的演示将有助于发展更有效的治疗方法。公共卫生相关性：内皮功能障碍对SCD病理生理学的贡献仍然很差。然而，已知有某些与SCD相关并发症（例如蛋白尿和肺动脉高压）的患者基于可溶性血管细胞粘附分子1（VCAM-1）的水平，表现出内皮功能障碍的证据。此外，这些患者表现出可溶性FMS样酪氨酸激酶-1（SFLT-1）水平升高的证据，这是VEGF受体家族的成员，众所周知会诱导内皮功能障碍。在此应用中，我们将通过解决以下具体目的来探讨内皮功能障碍以及SFLT-1/VEGF轴对SCD中蛋白尿的发病机理的贡献：我们将评估白蛋白尿素与内皮功能障碍的蛋白尿相关性，通过疾病的脑部疾病的疾病来评估蛋白外皮功能障碍，并评估无效我们将检验以下假设：在转基因镰状细胞小鼠中，通过SFLT-1改变VEGF的调节会导致肾小球内皮功能障碍和蛋白尿。最后，我们将评估阿托伐他汀对SCD患者内皮功能障碍和蛋白尿的影响。