Klotho and chronic kidney disease

Klotho 和慢性肾脏病

• 批准号: 10382243
• 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/10382243
• 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; 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. .

项目概要 慢性肾病 (CKD) 影响着大约 10% 的总人口。心脏病的患病率 CKD 患者的肥大明显增加，在 CKD 晚期高达 90%。 心血管疾病是CKD患者死亡的主要原因；其中心肌肥厚是 重要的根本原因。 CKD 中心脏肥大的危险因素还包括 CKD 特异性危险因素 作为常规危险因素（高血压和容量扩张等）。一些 CKD 特有的危险因素 已被提议，但他们的作用仍不确定。 Klotho 是一种膜蛋白，主要产生于 肾。 Klotho 的胞外结构域（可溶性 klotho；sKL）被释放到体循环中并 作为可溶性内分泌激素发挥作用。人类 CKD 患者中可溶性 Klotho 的血清水平降低 以及 CKD 小鼠模型中。我们最近报道 sKL 通过抑制 TRPC6 介导的保护心脏 异常的 Ca2+ 信号传导以及膜脂筏是 sKL 的受体。我们的首要假设是 sKL 结合脂筏发挥心脏保护作用，sKL 缺乏是尿毒症心脏肥大的一个原因。 为了支持这一假设以及开发潜在治疗方法的长期目标，我们提出了两个目标。 Aim-1 将识别和开发潜在的 sKL 模拟物，通过结合和靶向来发挥器官保护作用 唾液酸神经节苷脂和脂筏。我们将生产重组 sKL 和 sKL 模拟蛋白并检查它们 具有体外结合唾液酸神经节苷脂部分和体内保护器官的作用。 Aim-2将进一步阐明 sKL 调节 TRPC6 介导的异常 Ca2+ 信号传导的分子机制。支持者： 初步数据，我们将测试以下假设：含有 TRPC6 的囊泡预先对接至脂筏，并且 TRPC6 C 端区域的阳离子氨基酸与内部小叶中的 PIP3（受 PI3K 刺激）结合 筏膜的形成很重要。此外，我们将研究 DAG 刺激的分子机制 TRPC6囊泡胞吐作用，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。我们提出的小鼠研究将提供重要的临床前研究 可能导致治疗 CKD 诱发的心肌病的信息。此外，TRPC6 的上调 异常的 Ca2+-钙调神经磷酸酶-NFAT 信号传导对于维持和放大病理性心脏病至关重要 多种原因引起的肥大和重塑。基于 Klotho 的治疗策略可能适用于 多种心脏病。 。