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）影响大约10%的普通人群。CKD患者中心脏肥大的患病率显著增加，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潜在原因。CKD患者心脏肥大的危险因素包括CKD特异性危险因素和传统危险因素（高血压、体积扩张等）。已经提出了几个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的细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。可溶性Klotho的血清水平在人CKD患者和小鼠CKD模型中降低。我们最近报道了可溶性Klotho通过下调心脏中的TRPC 6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缺乏症导致了慢性肾脏病心脏肥大和心力衰竭的发病机制。目的-1将检查野生型、Klotho缺陷型和Klotho过表达小鼠的心脏肥大和心力衰竭，这些小鼠通过5/6肾切除术导致CKD。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TRPC 6通道和/或拮抗尿毒症心脏中上调的TGF β 1信号传导。Aim-2将检查Klotho替代是否可以防止CKD患者的心脏肥大和衰竭。我们将首先在分离的心肌细胞中进行结构-活性分析以鉴定Klotho抑制TRPC 6或拮抗TGF β 1信号传导的结构域。为了支持所鉴定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。此外，我们将产生纯化的特异性重组Klotho结构域蛋白，并在5/6肾切除的CKD小鼠中测试其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诱导的心肌病的治疗。此外，TRPC 6和异常Ca 2 +-钙调神经磷酸酶-NFAT信号传导的上调对于维持和放大病理性心脏肥大和由多种原因引起的重塑是至关重要的。基于Klotho的治疗策略可能适用于各种心脏疾病。