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。在CKD患者中，心脏肥厚的患病率明显增加，在CKD晚期高达90%。心血管疾病是CKD患者死亡的主要原因；其中心脏肥厚是一个重要的根本原因。CKD中心肌肥厚的危险因素包括CKD特异性危险因素以及常规危险因素（高血压、容积扩张等）。已经提出了几个ckd特定的危险因素，但它们的作用仍不确定。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，血清可溶性Klotho水平降低。我们最近报道了可溶性Klotho通过下调心脏中的TRPC6通道来保护心脏免受应激性心脏肥厚。因此，我们假设Klotho缺乏与CKD中心脏肥厚和心力衰竭的发病机制有关。Aim-1将检测通过5/6肾切除术致CKD的野生型、kloho缺陷型和kloho过表达型小鼠的心脏肥厚和心力衰竭。为了支持Klotho缺乏症导致尿毒症心肌病，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。Aim-2将研究Klotho替代是否能预防CKD患者的心脏肥厚和衰竭。我们将首先在分离的心肌细胞中进行结构-活性分析，以确定抑制TRPC6或拮抗TGFb1信号的Klotho结构域。为了支持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其心脏保护作用。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肌肥厚的治疗作用。我们在当前应用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，TRPC6的上调和Ca2+-钙调磷酸酶- nfat信号的异常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各种心脏疾病。