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: 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
• 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

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.

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.