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Klotho and Phosphate in Chronic Kidney Disease: Pathogenesis and Therapeutics

Klotho 和磷酸盐在慢性肾脏病中的作用：发病机制和治疗

基本信息

批准号：
9751266
负责人：
Ming-Chang Hu
金额：
$ 36.45万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-10 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751266
关键词：
Acceleration Affect Apoptosis Attenuated Automobile Driving Autophagocytosis BCL2 gene Biological Blood Vessels Bone Diseases Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cells Cessation of life Chronic Chronic Kidney Failure Clinical Data Combined Modality Therapy Complex Data Dialysis procedure Diet Disease Progression Disease model Dose Down-Regulation End stage renal failure Epidemic Epigenetic Process Equilibrium Etiology Foundations Functional disorder Genetic Transcription Genetically Modified Animals Heart Heart Diseases Heart Hypertrophy Homeostasis Hormones Human Hypermethylation Impairment In Vitro Individual Intervention Kidney Kidney Diseases Laboratories Mediating Mediator of activation protein Metabolic Diseases Methylation Minerals Modeling Molecular Mus Pathogenesis Pathologic Patients Phenotype Physiology Plasma Prevention Production Proteins Regimen Risk Factors Rodent Rodent Model Role Secondary to Secure Stem cells Supplementation System Testing Therapeutic Toxin Translating Translations Up-Regulation Uremia Vascular Diseases Vascular calcification Virulence Factors Work attenuation base cardiovascular risk factor coronary fibrosis efficacy testing improved in vitro Model in vivo inorganic phosphate mortality novel pre-clinical prevent promoter receptor restoration success therapeutic evaluation uremic cardiomyopathy

项目摘要

PROJECT SUMMARY Chronic kidney disease (CKD) has reached epidemic proportions globally. The single most important killer of CKD patients is cardiovascular disease (CVD) consisting of cardiac hypertrophy and fibrosis, and vascular calcification. More CKD patients die from CVD than reaching the need for dialysis. The treatment of traditional cardiovascular risk factors have met with limited success and we are in dire need to treat CKD-related CVD. Uremic cardiomyopathy is a complex metabolic disease with a panoply of underlying pathophysiologic factors. Our laboratory has focused on contributing mineral factors common to CVD and CKD-Mineral Bone Disorders (MBD) - which individually contributes to uremic cardiomyopathy, but each one also exacerbates the others creating a self-amplifying unrelenting vortex. We focus on the model that Klotho deficiency and phosphotoxicity exacerbate each other and both contribute to CVD. If we disrupt these disturbances simultaneously, it will be much more effective than manipulating them alone thus furnishing a novel and efficacious regimen to prevent and treat uremic cardiomyopathy. In Aim 1, we will use a well-established rodent model of CKD and uremic cardiomyopathy to test this therapeutic approach. These are empiric but important proof-of-concept studies to secure the utility of this approach. In Aim 2, we will examine the long sort after but yet unresolved question of the underlying mechanism of Klotho deficiency in CKD. We know that uremia, Klotho deficiency exacerbates phosphotoxicity by reducing phosphaturia but how Klotho is suppressed in CKD is not known. We will test the model that phosphate loading causes systemic Klotho deficiency by at least two mechanisms: direct inhibition of Klotho transcription via methylation of its promoter; and reduced Klotho shedding from the kidney using combined in vivo and in vitro approaches. Although Klotho deficiency per se have been shown to pathologic cardiac remodeling, the molecular mechanism(s) that mediate(s) its action is still an enigma. We constructed a model and propose that one principal mechanism is the balance between autophagy and apoptosis and Klotho holds the “toggle switch” by modifying the formation of the important autophagy complex Beclin 1/Bcl-2. In Aim 3, we will use both in vivo and in vitro models to test the paradigm. Using genetically modified animals, we will manipulate autophagy levels and test whether the protective action of Klotho is mediated by enhanced autophagy. We will use in vitro models to further test the model of phosphate loading and Klotho flipping the toggle switch in opposite directions. The proposed studies will uncover some fundamental biologic mechanisms of how Klotho is suppressed in CKD and phosphate loading, elucidate how Klotho protects the cell via autophagy flux, and finally provide the critical pre-clinical data to form the foundation for translation to therapy in human CKD and uremic cardiomyopathy.

项目概要慢性肾病（CKD）在全球范围内已达到流行病的程度。最重要的杀手 CKD患者是心血管疾病（CVD），包括心脏肥大和纤维化，以及血管钙化。死于 CVD 的 CKD 患者比需要透析的患者还要多。传统治疗心血管危险因素取得的成功有限，我们迫切需要治疗 CKD 相关的 CVD。尿毒症心肌病是一种复杂的代谢性疾病，具有多种潜在的病理生理因素。我们的实验室专注于贡献 CVD 和 CKD 常见的矿物质因子 - 矿物质骨疾病 (MBD) - 单独导致尿毒症心肌病，但每一种也会加剧其他疾病创造一个自我放大的无情漩涡。我们重点关注 Klotho 缺陷和磷毒性的模型两者相互加剧，共同导致 CVD。如果我们同时扰乱这些干扰，比单独操纵它们更有效，从而提供了一种新颖有效的方案来预防并治疗尿毒症心肌病。在目标 1 中，我们将使用成熟的 CKD 和尿毒症啮齿动物模型心肌病来测试这种治疗方法。这些是经验性但重要的概念验证研究确保该方法的实用性。在目标 2 中，我们将研究长期排序但尚未解决的问题 CKD 中 Klotho 缺陷的潜在机制。我们知道尿毒症，Klotho缺乏症会加剧通过减少磷酸尿而产生磷毒性，但 Klotho 在 CKD 中如何被抑制尚不清楚。我们将测试该模型表明，磷酸盐负荷至少通过两种机制导致系统性 Klotho 缺乏：直接抑制 Klotho 通过启动子甲基化进行转录；并减少 Klotho 从肾脏的脱落结合体内和体外方法。尽管 Klotho 缺陷本身已被证明会导致病理性心脏重塑，介导其作用的分子机制仍然是一个谜。我们构建了一个模型并提出一个主要机制是自噬和凋亡之间的平衡，Klotho 通过修改重要的自噬复合物 Beclin 1/Bcl-2 的形成来控制“切换开关”。瞄准 3、我们将使用体内和体外模型来测试范式。使用转基因动物，我们将操纵自噬水平并测试 Klotho 的保护作用是否是通过增强介导的自噬。我们将使用体外模型进一步测试磷酸盐负载和 Klotho 翻转模型向相反方向拨动开关。拟议的研究将揭示一些基本的生物学机制了解 Klotho 如何在 CKD 和磷酸盐负荷中受到抑制，阐明 Klotho 如何通过自噬保护细胞通量，并最终提供关键的临床前数据，为转化为人类治疗奠定基础 CKD 和尿毒症心肌病。