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：
10179360
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179360
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 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 stem cells 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.

项目摘要慢性肾脏疾病（CKD）在全球范围内已达到流行比例。最重要的杀手 CKD患者是心血管疾病（CVD），由心脏肥大和纤维化和血管组成钙化。 CKD患者死于CVD多于达到透析的需求。传统的处理心血管危险因素的成功有限，我们迫切需要治疗与CKD相关的CVD。尿毒症心肌病是一种复杂的代谢疾病，具有潜在的病理生理因素。我们的实验室重点是促进CVD和CKD时代骨骼疾病常见的矿物因素（MBD） - 单独有助于尿毒症心肌病，但每个人也会加剧其他人创建一个自我膨胀的无屈服涡流。我们专注于Klotho缺乏症和磷酸毒性的模型互相加剧，都会促进CVD。如果我们简单地破坏这些灾难，那将是比单独操纵它们更有效，因此提供了一种新颖有效的方案以防止并治疗尿毒症心肌病。在AIM 1中，我们将使用公认的CKD和尿毒症的啮齿动物模型心肌病以测试这种治疗方法。这些是经验性但重要的概念证明研究确保这种方法的实用性。在AIM 2中，我们将研究长期的，但尚未解决的问题 CKD中Klotho缺乏的基本机制。我们知道乌雷米亚，克洛索缺乏症加剧了通过减少磷酸来减少磷酸毒性，但尚不清楚克洛索如何抑制克洛托。我们将测试磷酸盐加载的模型至少通过两种机制导致全身性klotho缺乏：直接抑制通过其启动子的甲基化Klotho转录；并减少了使用肾脏从肾脏中脱落的结合体内和体外方法。尽管Klotho缺乏本身已显示为病理学心脏重塑，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和建议是一种主要机制是自噬和凋亡与klotho之间的平衡通过修改重要的自噬复合物beclin 1/bcl-2的形成来保持“切换开关”。目标 3，我们将使用体内和体外模型来测试范式。使用一般修改的动物，我们将操纵自噬水平，并测试克洛索的受保护作用是否通过增强介导自噬。我们将使用体外模型进一步测试磷酸盐载荷的模型和Klotho翻转切换开关在相反的方向上。拟议的研究将发现一些基本的生物学机制关于如何在CKD和磷酸盐载荷中抑制Klotho，阐明Klotho如何通过自噬保护细胞通量，最终提供关键的临床前数据，以构成翻译为人类治疗的基础 CKD和尿毒症心肌病。

项目成果

期刊论文数量（65）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（4）

αKlotho and vascular calcification: an evolving paradigm.

αKlotho 和血管钙化：一个不断发展的范例。

DOI：
10.1097/01.mnh.0000447024.97464.a3
发表时间：
2014-07
期刊：
Current opinion in nephrology and hypertension
影响因子：
3.2
作者：
Hu MC;Kuro-o M;Moe OW
通讯作者：
Moe OW

Dietary vitamin D interacts with high phosphate-induced cardiac remodeling in rats with normal renal function.

DOI：
10.1093/ndt/gfz156
发表时间：
2019-08
期刊：
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
影响因子：
0
作者：
M. Hu;R. Scanni;Jianfeng Ye;Jianning Zhang;Mingjun Shi;Jenny Maique;Brianna Flores;O. Moe;R. Krapf
通讯作者：
M. Hu;R. Scanni;Jianfeng Ye;Jianning Zhang;Mingjun Shi;Jenny Maique;Brianna Flores;O. Moe;R. Krapf

Alpha Klotho and phosphate homeostasis.

Alpha Klotho 和磷酸盐稳态