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Klotho and chronic kidney disease

Klotho 和慢性肾脏病

基本信息

批准号：
10615627
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
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615627
关键词：
Affect Age Months Amino Acids Binding Biochemical Biological Assay C-terminal Calcineurin Calcium Carbohydrates Cardiac Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cause of Death Cell Line Cell physiology Cessation of life Chronic Kidney Failure Circulation 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 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 Uremia Vesicle Vitamin D calcification cardioprotection experimental study imaging approach in vivo inorganic phosphate mimetics mortality mouse model mutant nuclear factors of activated T-cells paracrine pre-clinical premature programs receptor sialogangliosides supervitaminosis uremic cardiomyopathy

项目摘要

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. .

项目摘要慢性肾脏病（CKD）影响大约10%的普通人群。心脏病的患病率在CKD患者中肥大显著增加，在CKD的晚期达到高达90%。心血管疾病是CKD患者死亡的主要原因，其中心脏肥大是CKD患者死亡的主要原因。重要的根本原因。CKD患者心脏肥大的风险因素还包括CKD特异性风险因素作为常规危险因素（高血压和容量扩张等）。一些CKD特异性风险因素有人提出，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Klotho的细胞外结构域（可溶性klotho; sKL）被释放到体循环中，作为可溶性内分泌激素发挥作用。人CKD患者血清可溶性Klotho水平降低以及CKD小鼠模型中的情况。我们最近报道，sKL通过抑制TRPC 6介导的细胞膜脂筏是sKL的受体。我们的过度假设是 sKL结合脂筏发挥心脏保护作用，sKL缺乏是尿毒症性心脏肥大的原因。为了支持这一假设，沿着开发潜在治疗的长期目标，我们提出了两个目标。目的-1将鉴定和开发潜在的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，并检查它们的功能。在体外结合唾液酸神经节苷脂部分和在体内保护器官的作用。目标2将进一步阐明 sKL调节TRPC 6介导的异常Ca 2+信号传导的分子机制。支持初步数据，我们将测试假设，TRPC 6含有囊泡预先对接到脂筏， TRPC 6的C-末端区域中的阳离子氨基酸与内小叶中的PIP 3（由PI 3 K刺激）的结合筏膜是很重要的。此外，我们将研究DAG刺激的分子机制， TRPC 6囊泡胞吐，从而sKL抑制TRPC 6功能。我们将使用生化，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可能导致CKD诱导的心肌病治疗的信息。此外，TRPC 6的上调而异常的Ca 2 +-calcineurin-NFAT信号通路是维持和放大病理性心脏的关键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病。 .

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy.

低温电子显微镜揭示可溶性α-klotho 的构象景观。

DOI：
10.1101/2024.03.02.583144
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Schnicker,NicholasJ;Xu,Zhen;Amir,Mohammad;Gakhar,Lokesh;Huang,Chou-Long
通讯作者：
Huang,Chou-Long

Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease.

DOI：
10.1038/s41598-022-13390-z
发表时间：
2022-06-04
期刊：
Scientific reports
影响因子：
4.6
作者：
通讯作者：

Differential roles of WNK4 in regulation of NCC in vivo.

WNK4 在体内 NCC 调节中的不同作用。

DOI：
10.1152/ajprenal.00177.2017
发表时间：
2018
期刊：
American journal of physiology. Renal physiology
影响因子：
0
作者：
Yang,Yih-Sheng;Xie,Jian;Yang,Sung-Sen;Lin,Shih-Hua;Huang,Chou-Long
通讯作者：
Huang,Chou-Long

Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho.

DOI：
10.1016/j.kint.2016.09.039
发表时间：
2017-04
期刊：
Kidney international
影响因子：
19.6
作者：
Wu YL;Xie J;An SW;Oliver N;Barrezueta NX;Lin MH;Birnbaumer L;Huang CL
通讯作者：
Huang CL

Modeled structural basis for the recognition of α2-3-sialyllactose by soluble Klotho.

可溶性 Klotho 识别 α2-3-唾液酸乳糖的建模结构基础。

DOI：
10.1096/fj.201700043r
发表时间：
2017
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Wright,JonD;An,Sung-Wan;Xie,Jian;Yoon,Joonho;Nischan,Nicole;Kohler,JenniferJ;Oliver,Noelynn;Lim,Carmay;Huang,Chou-Long
通讯作者：
Huang,Chou-Long