The Alternative Pathway of Complement: A Potential Contributor to Adverse Outcomes in CKD

补体的替代途径：CKD 不良结果的潜在因素

• 批准号: 10657133
• 负责人: Diana I Jalal
• 金额: $ 62.94万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657133
• 关键词: Adipocytes; Affect; African American population; Albuminuria; Alternative Complement Pathway; Biological Assay; Biological Markers; Cardiovascular Diseases; Cells; Cessation of life; Chronic Disease; Chronic Kidney Failure; Clinical Trials; Complement; Complement Factor B; Complement Factor D; Complement Factor H; Data; Diabetes Mellitus; Disease Progression; End stage renal failure; Endothelium; Enzyme-Linked Immunosorbent Assay; Future; Generations; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Glomerular Filtration Rate; Hemolytic-Uremic Syndrome; Impairment; Individual; Inflammation; Injury; Intervention Trial; Kidney; Kidney Diseases; Link; Measures; Mediating; Mediator; Membrane; Morbidity - disease rate; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Pathway interactions; Patients; Plasma; Play; Population; Positioning Attribute; Predisposition; Proteome; Regulator Genes; Reproducibility; Research; Risk Factors; Role; Sampling; Serine Protease; Signal Transduction; Subgroup; Susceptibility Gene; Testing; Time; United States Department of Veterans Affairs; Vascular Diseases; Vesicle; adverse outcome; blood pressure intervention; brachial artery; cardiovascular disorder risk; clinical development; endothelial dysfunction; experimental study; gene complementation; genetic variant; high risk; in vivo; inhibitor; inhibitor therapy; meter; mortality; new therapeutic target; non-diabetic; particle; patient population; pre-clinical; predictive marker; rare variant; response; translational potential

PROJECT SUMMARY Chronic kidney disease (CKD) is a powerful mediator of morbidity and an independent predictor of death due to cardiovascular disease (CVD). Specifically, reduced glomerular filtration rate (GFR) is a powerful predictor of adverse outcomes. In this application we propose that the accumulation of Factor D (FD), which is filtered by the kidney and activates the alternative pathway (AP) of complement, represents an acquired dysregulation in the AP which then contributes to CVD and CKD progression. We compared the proteome of CKD patients to healthy controls. The strongest signal we observed was for components of the AP pathway. CKD patients had significantly higher levels of FD in circulating microparticles (sub-micrometer membrane vesicles that are shed from cells in response to activation or injury) and higher levels of Ba in the plasma (Ba is a biomarker of AP activation). FD activates the AP resulting in the generation of complement fragments including Ba. Factor H (FH) is the main inhibitor of the AP, but CKD was not associated with differences in the levels of FH. Our in vivo data indicate that even small increments in FD, if unopposed by adequate levels of FH, result in systemic AP activation. Furthermore, we found that plasma Ba levels are elevated in CKD and correlate with brachial artery flow-mediated dilation and with albuminuria, two indicators of endothelial dysfunction. Thus, increased levels of FD (as observed with reduced GFR in CKD) links CKD with systemic AP dysregulation, which may be an important mechanism of CVD and CKD progression in patients with CKD. Genetic variants in complement regulatory genes may also affect AP activation and may contribute to the risk of CVD and CKD progression in patients with CKD. Our group has identified several common CFH gene polymorphisms that associate with functional AP activation. Thus, our overall hypothesis is that CKD patients develop an acquired imbalance between FD and FH (high FD/FH ratio) leading to AP dysregulation (i.e., activation) such that biomarkers of the AP are predictive of CVD, CKD progression, and death in CKD. Secondarily, we hypothesize that individuals with a genetic propensity towards AP dysregulation will be the most susceptible to AP dysregulation in the setting of CKD. To test our hypothesis, we propose to utilize samples from two clinical trials: Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) and the Systolic Blood Pressure Interventional Trial (SPRINT). In aim 1, if CKD is independently associated with AP activation and determine if high FD/FH ratio predicts AP activation in CKD. In aims 2a and 2b we will examine whether plasma Ba independently predicts CVD or CKD progression in CKD patients, respectively. In aim 3, we will determine if CKD subjects with the highest degree of AP activation are enriched for genetic variants in CFH and other genes of the AP vs those with the lowest degree of AP activation. The proposed experiments will help us understand the mechanisms that underlie AP dysregulation in CKD and may define new therapeutic targets in this high-risk patient population.

项目摘要 慢性肾脏疾病（CKD）是发病率的有力中介，是由于 心血管疾病（CVD）。具体而言，降低的肾小球滤过率（GFR）是 不利的结果。在此应用中，我们建议因因子D（FD）的积累，该因子被过滤 肾脏并激活补体的替代途径（AP），表示在 AP随后有助于CVD和CKD进展。我们将CKD患者的蛋白质组与健康的蛋白质组进行了比较 控件。我们观察到的最强信号是对于AP途径的组件。 CKD患者有 循环微粒（脱落的亚微米膜囊泡）中的FD水平明显更高 从响应激活或损伤的细胞）和血浆中较高水平的BA（BA是AP的生物标志物 激活）。 FD激活AP，从而产生包括BA在内的补体片段。因子H（FH） 是AP的主要抑制剂，但CKD与FH水平的差异无关。我们的体内数据 表明即使是FD的小额增量，即使没有足够水平的FH，也会导致全身性AP 激活。此外，我们发现血浆BA水平在CKD中升高并与臂动脉相关 流介导的扩张和蛋白尿，这是内皮功能障碍的两个指标。因此，增加了 FD（如CKD中的GFR所观察到的那样）将CKD与全身性AP失调联系起来，这可能是 CKD患者CVD和CKD进展的重要机制。补体中的遗传变异 调节基因也可能影响AP激活，并可能导致CVD和CKD进展的风险 CKD患者。我们的小组已经确定了几种与之相关的常见CFH基因多态性 功能AP激活。因此，我们的总体假设是CKD患者患有获得性不平衡 在FD和FH（高FD/FH比）之间导致AP失调（即激活），以使其生物标志物的生物标志物 AP可以预测CKD中CVD，CKD进展和死亡。其次，我们假设个人 对于AP失调的遗传倾向将最容易受到AP失调的影响。 CKD。为了检验我们的假设，我们建议利用两个临床试验中的样本：退伍军人事务 糖尿病（VA Nephron-D）和收缩压干预试验（SPRINT）中的肾病。在 AIM 1，如果CKD与AP激活独立关联并确定高FD/FH比是否预测AP CKD激活。在AIMS 2A和2B中，我们将检查等离子BA是否独立预测CVD或CKD CKD患者的进展。在AIM 3中，我们将确定最高程度的CKD受试者 AP激活富含CFH的遗传变异和AP的其他基因与最低度的基因 AP激活。拟议的实验将帮助我们了解AP基础的机制 CKD的失调并可能定义这个高风险患者人群中的新治疗靶标。