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.

抽象的 尽管人们认识到镰状细胞疾病（SCD）的特征是 内皮功能障碍，内皮功能障碍对病理生理学的贡献 仍然定义很差。我们和其他人以前已经报告了 SCD患者的肺动脉高压和肾病，表明它们可能共享 类似的病理生理学。最近，我们发现SCD患者 大藻蛋白尿（尿白蛋白排泄> 300 mg/g肌酐）显着升高 两个可溶性血管细胞粘附分子1（VCAM-1）的水平，内皮的测量值 激活和可溶性FMS样酪氨酸激酶1（SFLT-1），VEGF受体的成员 家庭。已知SFLT-1通过在等离子体中的VEGF隔离而诱导内皮功能障碍 和/或通过形成非活性受体并减少信号转导。另外，我们 发现SFLT-1与SCD患者的可溶性VCAM-1显着相关。这个数据， 与其他疾病状态中SFLT-1与蛋白尿的缔合（例如 子痫前期表明，通过诱导内皮功能障碍，SFLT-1可能发挥重要作用 在SCD中的蛋白尿发展中的作用。 在当前应用中，我们将定义内皮功能障碍以及 SFLT-1/VEGF轴，用于SCD患者和转基因镰状细胞中蛋白尿的发病机理 老鼠。此外，我们将评估Atorvastatin的影响，Atorvastatin是一种已知的药物 减弱内皮功能障碍并减少SFLT-1释放，内皮功能障碍和 蛋白尿。有限的疗法可用于治疗SCD相关的肾病， 蛋白尿发病机理中内皮功能障碍作用的演示 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.