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: 8996584
• 负责人: DAVID R ARCHER
• 金额: $ 47.46万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996584
• 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; KDR gene; 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-1; Vascular Endothelial Growth Factors; Vasodilation; Work; abstracting; atorvastatin; base; brachial artery; defined contribution; effective therapy; endothelial dysfunction; 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 尽管人们认识到镰状细胞病(SCD)的特征是存在 内皮功能障碍--内皮功能障碍在疾病病理生理中的作用 仍然没有明确的定义。我们和其他人之前曾报道过一种 SCD患者的肺动脉高压和肾病，提示它们可能共享 类似的病理生理学。最近，我们发现SCD患者患有 大量蛋白尿(尿白蛋白排泄量；300毫克/克肌酐)显著增加 血管内皮细胞可溶性黏附分子-1(VCAM-1)水平 活化与血管内皮生长因子受体中的可溶性FMS样酪氨酸激酶-1(sFlt-1) 一家人。已知sFlt-1通过隔离血浆中的血管内皮生长因子而导致内皮功能障碍 和/或通过形成不活跃的受体和减少信号转导。此外，我们 发现SCD患者sFlt-1与sVCAM-1显著相关。这些数据， 结合sFlt-1与其他疾病状态(如 子痫前期)提示，通过诱导内皮功能障碍，sFlt-1可能在 在SCD蛋白尿发生发展中的作用。 在当前的应用中，我们将定义内皮功能障碍的贡献以及 SFlt-1/VEGF轴在SCD患者蛋白尿和转基因镰状细胞发病机制中的作用 老鼠。此外，我们将评估阿托伐他汀的效果，阿托伐他汀是一种已知的 减轻内皮功能障碍，减少sFlt-1的释放，对内皮功能障碍和 蛋白尿。由于可用于治疗SCD相关肾病的治疗方法有限， 内皮功能障碍在蛋白尿发病机制中的作用 促进开发更有效的治疗方法。

项目成果

Renal protection by atorvastatin in a murine model of sickle cell nephropathy.

阿托伐他汀在镰状细胞肾病小鼠模型中的肾脏保护作用。

• DOI: 10.1111/bjh.15157
• 发表时间: 2018-04
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Zahr RS;Chappa P;Yin H;Brown LA;Ataga KI;Archer DR
• 通讯作者: Archer DR

Does hydroxyurea prevent pulmonary complications of sickle cell disease?

羟基脲可以预防镰状细胞病的肺部并发症吗？

• DOI: 10.1182/asheducation-2014.1.432
• 发表时间: 2014
• 期刊: Hematology. American Society of Hematology. Education Program
• 作者: Buckner,TylerW;Ataga,KennethI
• 通讯作者: Ataga,KennethI

Alloimmunization is associated with older age of transfused red blood cells in sickle cell disease.

• DOI: 10.1002/ajh.24051
• 发表时间: 2015-08
• 期刊: AMERICAN JOURNAL OF HEMATOLOGY
• 影响因子: 12.8
• 作者: Desai, Payal C.;Deal, Allison M.;Pfaff, Emily R.;Qaqish, Bahjat;Hebden, Leyna M.;Park, Yara A.;Ataga, Kenneth I.
• 通讯作者: Ataga, Kenneth I.