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

基本信息

批准号：
9795895
负责人：
Anders Hayden Berg
金额：
$ 42.5万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9795895
关键词：
Adult Affect Age-Months Albumins Amino Acids Animal Model Animals Biological Assay Blood Tests Blood Urea Nitrogen Cardiac Cardiac Death Cardiac Function Study Cardiomyopathies Cardiovascular Diseases Cessation of life Chronic Kidney Failure Clinical Control Animal Creatinine Data Dialysis patients Dialysis procedure Diet Disease Disease Progression Echocardiography Expression Profiling Fibrosis Genetic Models German population Glomerulonephritis Glycosylated hemoglobin A Heart Heart failure Hemodialysis Homeostasis Hypertrophy Infusion procedures Kidney Diseases Kidney Failure Measures Mediating Mitochondria Modeling Modification Monitor Morbidity - disease rate Mus Myocardial Myocardial dysfunction Myopathy Nephrectomy Nutrient Nutritional Support Operative Surgical Procedures Oxidative Stress Participant Pathology Patients Post-Translational Protein Processing Predictive Value Prognostic Marker Proteins Renal function Risk Role Sampling Serum Signal Pathway Signal Transduction Stress cardiomyopathy Supplementation Taurine Testing Time Toxic effect Urea Uremia adverse outcome antioxidant enzyme clinical application density feeding glomerular filtration heart function indexing inhibitor/antagonist kidney dysfunction mRNA Expression mortality mouse model novel novel therapeutics outcome prediction overexpression podocyte post gamma-globulins prevent primary endpoint tool treatment group uremic cardiomyopathy wasting

项目摘要

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 5/6 nephrectomy and podocyte-specific COSMC-deficient mouse models of kidney failure mice which will be fed urea in their diet to test the effects of hyperuremia superimposed upon renal insufficiency. 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我们最近开发了一种氨甲酰白蛋白 (C-Alb) 检测方法，即血液检测。类似于“尿毒症的血红蛋白 A1c”。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。尿素对小鼠的过度氨甲酰化足以诱发小鼠的心脏功能障碍。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，以便将该测试的临床应用扩展到疾病早期阶段的患者，第二，我们要证明具体的治疗方法何时有机会阻止疾病进展。尿素对心脏的毒性并在 CKD 和氧化应激小鼠模型中研究其机制 AIM 1 将检验 C-Alb 是相关预后生物标志物的假设。不同阶段的非透析患者的死亡率、发病率、透析进展和蛋白质能量浪费 2-5 慢性肾脏病目标 1 将进一步比较 C-Alb 与标准临床相关的风险。尿毒症指标，以探讨 C-Alb 是否可能是早期开始透析的更好指标，并将检验高 C-Alb 与特定氨基酸和其他氨基酸缺乏有关的假设代表靶向营养疗法候选者的必需营养素将寻求良好发展。控制尿素诱发的心肌病小鼠模型，以证明尿素对心脏的直接毒性并研究潜在的机制：通过诱导循环尿素的单独增加。给肾功能下降的小鼠或对心脏线粒体氧化敏感的小鼠喂食尿素压力会导致心肌病和心力衰竭，类似于慢性肾病患者的情况。目标 2(a) 将利用 5/6 肾切除术和足细胞特异性 COSMC 缺陷小鼠肾衰竭模型在饮食中喂食尿素的小鼠，以测试高尿血症对肾功能不全的影响。将通过超声心动图监测动物的心功能差异，并研究介导尿素毒性的心肌信号通路目标 2(b) 将利用具有心脏功能的小鼠模型。 PGC-1α 共激活剂的特异性缺乏这些动物的心脏线粒体氧化增加。给这些动物喂食尿素将测试其贡献。尿素对正常肾功能障碍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。