Klotho and chronic kidney disease

Klotho 和慢性肾脏病

• 批准号: 10133460
• 负责人: Chou-Long Huang
• 金额: $ 52.08万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133460
• 关键词: Affect; Age-Months; Amino Acids; Binding; Biochemical; Biological Assay; Blood Circulation; C-terminal; Calcineurin; Calcium; Carbohydrates; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cations; Cause of Death; Cell Line; Cell physiology; Cessation of life; Chronic Kidney Failure; Clinical Data; Data; Development; Docking; Down-Regulation; Electrophysiology (science); Endocrine; Epidemic; Exocytosis; Extracellular Domain; Extracellular Space; Fibroblast Growth Factor Receptors; General Population; Goals; Growth; Growth Factor; Heart; Heart Diseases; Heart Hypertrophy; Homeostasis; Hormones; Human; Hypercalcemia; Hypertension; Hypertrophy; In Vitro; Integral Membrane Protein; Kidney; Lead; Length; Lipid Binding; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Membrane Proteins; Modeling; Molecular; Mus; Muscle Contraction; Mutation; Myocardial dysfunction; Organ; Pathogenesis; Pathologic; Patients; Permeability; Phase; Phosphotransferases; Play; Prevalence; Principal Investigator; Proteins; Public Health; Publishing; Recombinants; Regulation; Reporting; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Structure; Tertiary Protein Structure; Testing; Therapeutic; Tissues; Up-Regulation; Vesicle; Vitamin D; base; calcification; cardioprotection; experimental study; imaging approach; in vivo; inorganic phosphate; mimetics; mortality; mouse model; mutant; paracrine; pre-clinical; premature; programs; receptor; sialogangliosides; supervitaminosis; uremic cardiomyopathy

Project Summary 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 (soluble klotho; sKL) 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 sKL protects the heart by inhibiting TRPC6-mediated abnormal Ca2+ signaling and that membrane lipid rafts are receptors for sKL. Our over-arching hypothesis is that sKL binds lipid rafts to exert cardiac protection and that sKL deficiency is a cause of uremic cardiac hypertrophy. To support this hypothesis along with the long-term goal of developing potential treatment, we propose two aims. Aim-1 will identify and develop potential sKL-mimetic that exerts organ protection by binding and targeting sialogangliosides and lipid rafts. We will produce recombinant sKL and sKL-mimetic proteins and examine their effects to bind sialoganglioside moiety in vitro and to protect organ in vivo. Aim-2 will further elucidate the molecular mechanism for sKL regulation of TRPC6-mediated abnormal Ca2+ signaling. Supported by the preliminary data, we will test the hypothesis that TRPC6-containing vesicles are pre-docked to lipid rafts and that binding of cationic amino acids in the C-terminal region of TRPC6 to PIP3 (stimulated by PI3K) in the inner leaflet of raft membrane is important. Furthermore, we will examine molecular mechanism by which DAG stimulates TRPC6 vesicle exocytosis, thereby sKL inhibits TRPC6 function. We will use combined biochemical, electrophysiological, and imaging approaches. Our proposed studies in mice 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. .

项目摘要 慢性肾脏疾病（CKD）影响了大约10％的普通人群。心脏的患病率 CKD患者的肥大明显增加，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也包括CKD特异性危险因素 作为常规风险因素（高血压和体积扩张等）。几个CKD特异性危险因素具有 被提出了，但他们的角色仍然没有定论。克洛索（Klotho）是一种主要生产的膜蛋白 肾。克洛索（可溶性klotho; skl）的细胞外域被释放到系统性循环中， 充当可溶性内分泌激素。人CKD患者的血清可溶性klotho水平降低 在CKD的鼠标模型中。我们最近报道SKL通过抑制TRPC6介导的保护心脏 CA2+信号异常和膜脂筏是SKL的受体。我们的整理假设是 SKL结合脂质筏以施加心脏保护，而SKL缺乏症是尿毒症心脏肥大的原因。 为了支持这一假设以及开发潜在治疗的长期目标，我们提出了两个目标。 AIM-1将识别并开发潜在的SKL模拟，通过结合和靶向来施加器官保护 唾液酸内囊剂和脂质筏。我们将产生重组SKL和SKL模拟蛋白，并检查它们 在体外结合唾液酸固醇部分并保护器官在体内的影响。 AIM-2将进一步阐明 TRPC6介导的异常Ca2+信号传导的SKL调节的分子机制。由 初步数据，我们将测试以下假设：含TRPC6的囊泡被预先添加到脂质筏上，并且 Trpc6的C末端区域中阳离子氨基酸与PIP3的C末端区域（由PI3K刺激） 筏膜的重要性很重要。此外，我们将检查DAG刺激的分子机制 TRPC6囊泡胞吐作用，因此SKL抑制TRPC6功能。我们将使用合并的生化， 电生理和成像方法。我们在小鼠中提出的研究将提供重要的临床前 可能导致CKD诱导的心肌病治疗的信息。此外，TRPC6的上调 和异常的Ca2+-Calcineurin-NFAT信号对于维持和扩增病理心脏至关重要 肥大和从不同原因进行重塑。基于Klotho的治疗策略可能适用于 多样化的心脏病。 。