Klotho and Chronic Kidney Disease

Klotho 和慢性肾脏病

• 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
• 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

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）：慢性肾脏疾病（CKD）影响了大约10％的普通人群。 CKD患者的心脏肥大的患病率显着增加，在CKD的晚期阶段达到高达90％。心血管疾病是CKD患者死亡的主要原因。其中心脏肥大是重要的根本原因。 CKD中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（高血压和体积扩张等）。已经提出了几个特定于CKD的风险因素，但其角色仍然尚无定论。克洛索（Klotho）是一种主要在肾脏中产生的膜蛋白。克洛索的细胞外域被释放到系统性循环中，并用作可溶性内分泌激素。人CKD患者和CKD小鼠模型中的血清可溶性克洛索水平降低。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压力诱导的心脏肥大。因此，我们假设Klotho缺乏症有助于CKD中心脏肥大和心力衰竭的发病机理。 AIM-1将检查野生型，klotho缺陷型和klotho过表达的小鼠的心脏肥大和心力衰竭，使CKD通过5/6肾切除术。为了支持Klotho缺乏症有助于尿毒症心肌病，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TGFB1对TGFB1的拮抗作用。 AIM-2将检查Klotho替代方法是否可以防止CKD中的心脏肥大和失败。我们将执行结构活性分析，以识别Klotho的结构域，该结构域抑制TRPC6或首先在分离的心肌细胞中拮抗TGFB1信号传导。为了支持已识别域在体内心脏保护中的关键作用，我们将生成表达域并测试心脏保护的转基因小鼠。此外，我们将生成纯化的特定重组klotho结构蛋白，并测试其在逆转或预防5/6肾切除型CKD小鼠中的治疗作用。我们在当前应用中对小鼠的拟议研究将提供重要的临床前信息，这可能导致CKD诱导的心肌病的治疗。此外，TRPC6和异常Ca2+-Calcineurin-NFAT信号的上调对于维持和扩增病理心脏肥大并从各种原因中重塑至关重要。基于Klotho的治疗策略可能适用于各种心脏病。