Protein carbamylation and uremic cardiomyopathy in chronic kidney disease

慢性肾脏病中的蛋白质氨甲酰化与尿毒症心肌病

• 批准号: 9324463
• 负责人: Anders Hayden Berg
• 金额: $ 43.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324463
• 关键词: Ablation; Adult; Affect; Albumins; Amino Acids; Animal Model; Animals; Apoptosis; Biological Assay; Blood Tests; Blood Urea Nitrogen; CASP8 gene; Cardiac; Cardiac Death; Cardiac Function Study; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Chimeric Proteins; Chronic Kidney Failure; Clinical; Control Animal; Creatinine; Dialysis patients; Dialysis procedure; Diet; Disease; Disease Progression; Dose; Echocardiography; Fibrosis; Functional disorder; German population; Glycosylated hemoglobin A; Heart; Heart failure; Hemodialysis; Hypertrophy; Infusion procedures; Kidney; Kidney Diseases; Kidney Failure; Measures; Mediating; Methods; Mitochondria; Modification; Molecular Profiling; Monitor; Morbidity - disease rate; Mus; Myocardial; Myocardial dysfunction; Myopathy; Nutrient; Nutritional Support; Outcome; Oxidative Stress; Participant; Pathology; Patients; Post-Translational Protein Processing; Potassium Phosphate; Predictive Value; Prognostic Marker; Proteins; Renal function; Risk; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Staging; Stress cardiomyopathy; Supplementation; Tacrolimus Binding Proteins; Testing; Time; Toxic effect; Urea; Uremia; adverse outcome; antioxidant enzyme; clinical application; density; feeding; indexing; inhibitor/antagonist; mRNA Expression; mortality; mouse model; novel; novel therapeutics; podocyte; post gamma-globulins; prevent; tool; treatment group; uremic cardiomyopathy; wasting

PROJECT SUMMARY/ABSTRACT There is growing evidence that protein modification by urea (carbamylation) contributes to uremic cardiomyopathy and mortality. We recently developed an assay for carbamylated albumin (C-Alb), a blood test similar to “hemoglobin A1c for uremia.” We have shown that C-Alb values are predictive of risk of heart failure and death from cardiac causes in patients on hemodialysis and that amino acid deficiencies are critical determinants of carbamylation, and C-Alb can be reduced by amino acid scavenger therapy. Moreover, hypercarbamylation by urea in mice is sufficient to induce cardiac dysfunction in mice. This proposal seeks to investigate whether C-Alb also predicts outcomes in patients with chronic kidney disease prior to initiation of dialysis therapy in order to extend the clinical applications of this test to patients in the earlier stages of disease, when changes in treatment have a chance to prevent disease progression. Second, we want to prove the specific toxicity of urea on the heart and investigate its mechanisms in mouse models of CKD and oxidative stress-associated cardiomyopathy. AIM 1 will test the HYPOTHESIS that C-Alb is a prognostic biomarker associated with mortality, morbidity, progression to dialysis, and protein energy wasting in non-dialyzed patients with stages 2-5 chronic kidney disease. Aim 1 will further compare the risk associated with C-Alb to that of standard clinical indicators of uremia in order to probe whether C-Alb may be a superior indication of early initiation of dialysis, and will test the hypothesis that high C-Alb is associated with deficiencies of specific amino acids and other essential nutrients which represent candidates for targeted nutritional therapies. AIM 2 will seek to develop well controlled mouse models of urea-induced cardiomyopathy in order to prove the direct toxicity of urea on the heart and to study potential mechanisms. Our HYPOTHESIS is that inducing isolated increases in circulating urea by feeding urea to mice with reduced kidney function or to mice with sensitivity to cardiac mitochondrial oxidative stress will produce cardiomyopathy and heart failure similar to that seen in patients with chronic kidney disease. Aim 2(a) will utilize the POD-ATTAC mouse model of inducible kidney failure mice which will be fed urea in their diet to test the effects of hyperuremia superimposed upon renal insufficiency. Control animals will be similarly treated with podocyte ablation but fed normal diets. Animals will be monitored by echocardiography for differences in cardiac function, and studied for differences in myocardial signaling pathways which mediate urea's toxicity. Aim 2(b) will utilize a mouse model with a cardiac-specific deficiency of PGC-1α coactivator. These animals suffer from increased cardiac mitochondrial oxidative stress and are prone to stress-induced cardiomyopathy. Feeding urea to these animals will test the contribution of urea to cardiac oxidative stress and myopathy in an animal with normal kidney dysfunction, further isolating the effect of urea on the heart.

项目概要/摘要 越来越多的证据表明尿素（氨甲酰化）对蛋白质的修饰会导致尿毒症 心肌病和死亡率。我们最近开发了一种氨基甲酰化白蛋白 (C-Alb) 检测方法，这是一种血液检测 类似于“尿毒症的糖化血红蛋白”。我们已经证明 C-Alb 值可以预测心力衰竭的风险 血液透析患者因心脏原因死亡，氨基酸缺乏至关重要 氨甲酰化的决定因素和 C-Alb 可以通过氨基酸清除剂治疗来减少。而且， 尿素对小鼠的过度氨甲酰化足以诱导小鼠心脏功能障碍。该提案旨在 研究 C-Alb 是否也可以在开始治疗之前预测慢性肾病患者的结果 透析治疗，以将该测试的临床应用扩展到早期阶段的患者 当改变治疗方法有机会阻止疾病进展时。其次，我们要证明 尿素对心脏的特异性毒性及其在 CKD 和氧化小鼠模型中的机制研究 应激相关性心肌病。 AIM 1 将检验 C-Alb 是预后生物标志物的假设 与非透析患者的死亡率、发病率、透析进展和蛋白质能量浪费相关 患有2-5期慢性肾病的患者。目标 1 将进一步比较与 C-Alb 相关的风险 尿毒症的标准临床指标，以探讨 C-Alb 是否可能是尿毒症的优越指征 尽早开始透析，并将检验高 C-Alb 与特定特定物质缺乏相关的假设 氨基酸和其他必需营养素代表了靶向营养疗法的候选者。目标2 将寻求开发良好控制的尿素诱发心肌病小鼠模型，以证明直接作用 尿素对心脏的毒性并研究潜在机制。我们的假设是诱导孤立 通过给肾功能下降的小鼠或对尿素敏感的小鼠喂食尿素来增加循环尿素 心脏线粒体氧化应激会导致心肌病和心力衰竭，类似于在 慢性肾脏病患者。目标 2(a) 将利用 POD-ATTAC 小鼠诱导肾模型 失败的小鼠将在饮食中喂食尿素，以测试高尿毒症对肾脏的影响 不足。对照动物将接受类似的足细胞消融治疗，但喂食正常饮食。动物会 通过超声心动图监测心脏功能的差异，并研究心肌的差异 介导尿素毒性的信号通路。目标 2(b) 将利用具有心脏特异性的小鼠模型 PGC-1α 共激活剂缺乏。这些动物的心脏线粒体氧化应激增加 并且容易患压力诱发的心肌病。给这些动物喂食尿素将测试其贡献 尿素对具有正常肾功能障碍的动物的心脏氧化应激和肌病的影响，进一步分离 尿素对心脏的影响。