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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。。

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