Klotho and Chronic Kidney Disease

Klotho 和慢性肾脏病

• 批准号: 9324978
• 负责人: Chou-Long Huang
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF IOWA
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324978
• 关键词: Affect; Age-Months; Aging; 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; 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; Myocardial dysfunction; Nephrectomy; Pathogenesis; Pathologic; Patients; Phenotype; Play; Prevalence; Public Health; Recombinants; Reporting; Risk Factors; Role; Serum; Signal Transduction; Stress; Structure; Sudden Death; Tertiary Protein Structure; Testing; Therapeutic; Transgenic Mice; Up-Regulation; Ventricular; Weight; age effect; 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; uremic cardiomyopathy

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(申请人提供)：慢性肾脏疾病(CKD)影响大约10%的一般人口。CKD患者心肌肥厚的发生率明显增加，在CKD晚期高达90%。心血管疾病是CKD患者的主要死亡原因，其中心肌肥厚是一个重要的潜在原因。CKD心肌肥厚的危险因素包括CKD特有的危险因素和常规危险因素(高血压和容量扩张等)。已经提出了几个CKD特有的危险因素，但它们的作用仍不确定。Klotho是一种主要在肾脏产生的膜蛋白。Klotho的胞外区被释放到体循环中，作为一种可溶的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，可溶性Klotho通过下调心脏中TRPC6通道的表达来保护心脏免受应激诱导的心肌肥厚。因此，我们假设Klotho缺乏与慢性肾脏病心肌肥厚和心力衰竭的发病机制有关。AIM-1将检测野生型、Klotho缺陷和Klotho过表达小鼠的心肌肥大和心力衰竭，这些小鼠通过5/6肾切除术获得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TRPC6通道和/或拮抗尿毒症心脏上调的TGFb1信号。AIM-2将研究Klotho替代物是否能预防慢性肾脏病患者的心肌肥厚和衰竭。我们将进行结构活性分析，以确定Klotho的结构域，它首先在分离的心肌细胞中抑制TRPC6或拮抗TGFb1信号。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并测试心脏保护的转基因小鼠。此外，我们将制备纯化的特异性重组Klotho结构域蛋白，并检测其对5/6肾切除CKD小鼠心肌肥厚的逆转或预防作用。我们目前在小鼠身上进行的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的上调和钙-钙调神经磷酸酶-NFAT信号的异常对于维持和放大各种原因引起的病理性心肌肥厚和重构至关重要。基于Klotho的治疗策略可能适用于各种心脏疾病。