Klotho and chronic kidney disease

Klotho 和慢性肾脏病

• 批准号: 9899972
• 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/9899972
• 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)约占总人口的10%。心脏病的患病率 CKD患者肥大程度明显增加，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 重要的潜在原因。CKD患者心肌肥大的危险因素也包括CKD特有的危险因素 作为常规危险因素(高血压和体量扩张等)。几个CKD特有的风险因素 已经提出，但他们的作用仍然没有定论。Klotho是一种膜蛋白，主要产生于 肾脏。Klotho(可溶性Klotho；SKL)的胞外区被释放到体循环中，并 作为一种可溶的内分泌激素。慢性肾脏病患者血清可溶性Klotho水平降低 在CKD的小鼠模型中也是如此。我们最近报道，SKL通过抑制TRPC6介导的途径来保护心脏 钙信号异常，膜脂筏是SKL的受体。我们最重要的假设是 SKL结合脂筏以发挥心脏保护作用，SKL缺乏是尿毒症心肌肥厚的原因之一。 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将识别和开发潜在的SKL模拟物，通过结合和靶向发挥器官保护作用 唾液神经节苷脂和脂筏。我们将生产重组SKL和SKL模拟蛋白，并检测它们的 唾液神经节苷脂部分体外结合及体内器官保护作用。AIM-2将进一步阐明 SKL调节TRPC6介导的异常钙信号的分子机制。由 初步数据，我们将检验含有TRPC6的囊泡预先对接到脂筏上的假设，并且 内叶TRPC6 C-末端阳离子氨基酸与PIP3的结合(受PI3K刺激) 木筏膜的稳定性是重要的。此外，我们还将研究DAG刺激的分子机制 TRPC6囊泡胞吐，从而SKL抑制TRPC6功能。我们将使用组合生化， 电生理学和成像方法。我们提出的对小鼠的研究将为临床前提供重要的 可能导致CKD所致心肌病治疗的信息。此外，TRPC6的上调 而钙-钙调神经磷酸酶-NFAT信号的异常对于维持和放大病理性心脏 各种原因引起的肥大和重塑。基于Klotho的治疗策略可能适用于 各种心脏疾病。 。