Klotho and Chronic Kidney Disease

Klotho 和慢性肾脏病

基本信息

批准号：
8752459
负责人：
Chou-Long Huang
金额：
$ 23.85万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-20 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8752459
关键词：
Affect Age-Months Antihypertensive Agents Blood Circulation Calcineurin Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cause of Death Cells Cessation of life Chronic Kidney Failure Defect Development Diet Diuretics Down-Regulation Endocrine Epidemic Exhibits Extracellular Domain Functional disorder Gene Expression General Population Growth Heart Heart Diseases Heart Hypertrophy Heart failure Hormones Human Hypertension In Vitro Injury Integral Membrane Protein Isoproterenol Kidney Knockout Mice Lead Liquid substance Mediating Membrane Proteins Molecular Morphology Mus Muscle Cells Nephrectomy Pathogenesis Patients Phenotype Play Prevalence Public Health Recombinants Reporting Risk Factors Role Serum Signal Transduction Staging Stress Structure Sudden Death Tertiary Protein Structure Testing Therapeutic Transgenic Mice Up-Regulation Ventricular Weight age effect age related anti aging base blood pressure regulation design fibroblast growth factor 23 in vivo inorganic phosphate mortality mouse model nuclear factors of activated T-cells overexpression pre-clinical premature prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) affects approximately 10% of the general population. The prevalence of cardiac hypertrophy is markedly increased in CKD patients, reaching as high as 90% in advanced stages of CKD. Cardiovascular disease is the main cause of death for CKD patients; among which cardiac hypertrophy is an important underlying cause. Risk factors for cardiac hypertrophy in CKD include CKD-specific risk factors as well as conventional risk factors (hypertension and volume expansion, etc). Several CKD-specific risk factors have been proposed but their roles remain inconclusive. Klotho is a membrane protein predominantly produced in the kidney. The extracellular domain of Klotho is released into the systemic circulation and functions as a soluble endocrine hormone. Serum levels of soluble Klotho are decreased in human CKD patients and in mouse models of CKD. We recently reported that soluble Klotho protects the heart against stress-induced cardiac hypertrophy by downregulation of TRPC6 channels in the heart. Thus, we hypothesize that Klotho deficiency contributes to the pathogenesis of cardiac hypertrophy and heart failure in CKD. Aim-1 will examine cardiac hypertrophy and heart failure in wild-type, Klotho-deficient, and Klotho-overexpressing mice rendered CKD by 5/6 nephrectomy. To support that Klotho deficiency contributes to uremic cardiomyopathy, we will further examine the molecular mechanism by which Klotho protects uremic cardiomyopathy, including inhibition of cardiac TRPC6 channels and/or antagonism of TGFb1 signaling upregulated in the uremic hearts. Aim-2 will examine whether Klotho replacement protects against cardiac hypertrophy and failure in CKD. We will perform structure-activity analysis to identify the domain of Klotho that inhibits TRPC6 or antagonizes TGFb1 signaling first in isolated cardiomyocytes. To support the critical role of identified domain in cardioprotection in vivo, we will generate transgenic mice that express the domain and test for cardioprotection. Furthermore, we will generate purified specific recombinant Klotho domain protein and test its therapeutic role in reversing or preventing cardiac hypertrophy in 5/6 nephrectomized CKD mice. Our proposed studies in mice in the current application will provide important pre-clinical information that may lead to treatment of CKD-induced cardiomyopathy. Furthermore, upregulation of TRPC6 and abnormal Ca2+-calcineurin-NFAT signaling is critical for sustaining and amplifying pathological cardiac hypertrophy and remodeling from diverse causes. Klotho-based therapeutic strategies may be applicable to diverse cardiac diseases.

描述（由申请人提供）：慢性肾病 (CKD) 影响大约 10% 的总人口。 CKD 患者心脏肥大的患病率显着升高，在 CKD 晚期高达 90%。心血管疾病是CKD患者死亡的主要原因；其中心脏肥大是一个重要的根本原因。 CKD 心脏肥大的危险因素包括 CKD 特异性危险因素以及常规危险因素（高血压、容量扩张等）。已经提出了几种 CKD 特定的风险因素，但它们的作用仍然没有定论。 Klotho 是一种主要在肾脏中产生的膜蛋白。 Klotho 的胞外结构域被释放到体循环中，并作为可溶性内分泌激素发挥作用。在人类 CKD 患者和 CKD 小鼠模型中，可溶性 Klotho 的血清水平降低。我们最近报道，可溶性 Klotho 通过下调心脏中的 TRPC6 通道来保护心脏免受应激诱导的心脏肥大。因此，我们假设 Klotho 缺乏导致 CKD 中心脏肥大和心力衰竭的发病机制。 Aim-1 将检查通过 5/6 肾切除术导致 CKD 的野生型、Klotho 缺陷型和 Klotho 过度表达小鼠的心脏肥大和心力衰竭。为了支持 Klotho 缺乏导致尿毒症心肌病，我们将进一步研究 Klotho 保护尿毒症心肌病的分子机制，包括抑制心脏 TRPC6 通道和/或拮抗尿毒症心脏中上调的 TGFb1 信号传导。 Aim-2 将检查 Klotho 替代疗法是否可以预防 CKD 中的心脏肥大和衰竭。我们将进行结构活性分析，以确定首先在分离的心肌细胞中抑制 TRPC6 或拮抗 TGFb1 信号传导的 Klotho 结构域。为了支持已识别的结构域在体内心脏保护中的关键作用，我们将产生表达该结构域的转基因小鼠并测试心脏保护作用。此外，我们将生成纯化的特异性重组 Klotho 结构域蛋白，并测试其在 5/6 肾切除 CKD 小鼠中逆转或预防心脏肥大的治疗作用。我们在当前申请中提出的小鼠研究将提供重要的临床前信息，可能导致 CKD 诱发的心肌病的治疗。此外，TRPC6 和异常 Ca2+-钙调神经磷酸酶-NFAT 信号传导的上调对于维持和放大各种原因引起的病理性心脏肥大和重塑至关重要。基于 Klotho 的治疗策略可能适用于多种心脏病。