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.

项目概要 慢性肾病 (CKD) 是发病率的有力调节因素，也是因慢性肾病导致的死亡的独立预测因子 心血管疾病（CVD）。具体来说，肾小球滤过率（GFR）降低是一个强有力的预测因素 不良后果。在此应用中，我们建议因子 D (FD) 的累积，其通过 肾脏并激活补体的替代途径（AP），代表获得性的补体失调 AP 进而导致 CVD 和 CKD 进展。我们将 CKD 患者与健康人的蛋白质组进行了比较 控制。我们观察到的最强信号是 AP 途径的成分。 CKD 患者有 循环微粒（脱落的亚微米膜囊泡）中 FD 水平显着升高 来自细胞对激活或损伤的反应）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，导致包括 Ba 在内的补体片段的生成。 H 因子 (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 FD 的小增量，如果没有足够水平的 FH 的抵抗，也会导致系统性 AP 激活。此外，我们发现 CKD 患者血浆 Ba 水平升高，且与肱动脉相关 血流介导的扩张和蛋白尿是内皮功能障碍的两个指标。因此，增加的水平 FD（观察到 CKD 中 GFR 降低）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 慢性肾病患者。我们的小组已经确定了几种常见的 CFH 基因多态性，这些多态性与 功能性 AP 激活。因此，我们的总体假设是 CKD 患者会出现一种获得性失衡 FD 和 FH 之间的差异（高 FD/FH 比率）导致 AP 失调（即激活），从而使 AP 可预测 CVD、CKD 进展和 CKD 死亡。其次，我们假设个体 具有 AP 失调遗传倾向的人在该环境中最容易受到 AP 失调的影响 慢性肾病。为了检验我们的假设，我们建议利用两项临床试验的样本：退伍军人事务部 糖尿病肾病 (VA NEPHRON-D) 和收缩压干预试验 (SPRINT)。在 目标 1，如果 CKD 与 AP 激活独立相关，并确定高 FD/FH 比率是否预测 AP CKD 中的激活。在目标 2a 和 2b 中，我们将检查血浆 Ba 是否独立预测 CVD 或 CKD CKD 患者的进展情况。在目标 3 中，我们将确定 CKD 受试者是否具有最高程度的 与程度最低的那些相比，CFH 和 AP 的其他基因中的遗传变异丰富了 AP 激活 AP 激活。所提出的实验将帮助我们了解 AP 背后的机制 CKD 的失调可能会为这一高危患者群体确定新的治疗靶点。