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Hyperphosphatemia Contributes to Systemic Inflammation and Anemia in Chronic Kidney Disease

高磷血症导致慢性肾脏病的全身炎症和贫血

基本信息

批准号：
10604327
负责人：
Christian Faul
金额：
$ 36.27万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10604327
关键词：
Adenine Adult Affect Age Anemia Animal Model Biological Markers Blocking Antibodies Blood Calcineurin Cardiac Myocytes Cardiovascular Diseases Cell Surface Receptors Cells Cessation of life Chronic Kidney Failure Communication Control Animal Diet Drug Targeting Enzyme-Linked Immunosorbent Assay Epidemic FGF2 gene FGFR4 gene Fibroblast Growth Factor Receptors Health Heart Heart Hypertrophy Hepatic Hepatocyte Hormones In Vitro Inflammatory Injections Injury to Kidney Inorganic Phosphate Transporter Integral Membrane Protein Interleukin-6 Kidney Knock-out Link Liver Mediating Mediator Metabolism Minerals Mitogen-Activated Protein Kinases Modeling Molecular Mus Muscular Atrophy PTH gene Pathologic Pathology Patients Phospholipase Physiological Production Protein Isoforms Reporting Research Proposals Rodent Model Serum Severity of illness Signal Induction Signal Pathway Signal Transduction Skeletal muscle injury Smooth Muscle Myocytes Source Testing Therapeutic Tissues Tubular formation Vascular Smooth Muscle Vascular calcification Vitamin D Wild Type Mouse Work bone cancer clinical trial cell type comorbidity cytokine fibroblast growth factor 23 fibroblast growth factor receptor 4 hepcidin in vivo inhibitor inorganic phosphate iron deficiency iron metabolism knock-down mortality mortality risk mouse model muscle strength novel novel therapeutic intervention nuclear factors of activated T-cells paracrine pharmacologic premature prevent protective effect protein function receptor release factor skeletal muscle metabolism skeletal muscle wasting systemic inflammatory response tissue injury uptake

项目摘要

PROJECT SUMMARY Chronic kidney disease (CKD) is a health epidemic that increases risk of death due to various comorbidities. Alterations in mineral metabolism are a hallmark of advanced CKD, where hyperphosphatemia and the associated increase in serum concentrations of fibroblast growth factor (FGF) 23 have been suspected to directly contribute to tissue damage and mortality, but the underlying mechanisms are not fully understood. We previously found that by targeting cardiac myocytes via FGF receptor (FGFR) 4, elevated FGF23 activates a specific signaling pathway and induces cardiac hypertrophy in rodent models of CKD. We also reported that by activating this mechanism, FGF23 can directly target hepatocytes. However, the consequences of FGF23’s hepatic action have not been investigated in vivo. Compared to FGF23, much less is known about the direct pathologic actions of elevated serum phosphate. Mechanistic studies have shown that by targeting vascular smooth muscle cells via specific phosphate transporters and signal mediators, elevated phosphate can cause vascular calcification. Direct actions of elevated phosphate concentrations on the heart are not understood, and potential effects of phosphate on the liver have not been analyzed so far. Our preliminary in vitro studies in primary mouse hepatocytes indicate that phosphate and FGF23 can both induce the expression of inflammatory cytokines, such as interleukin 6 (IL6), and of hepcidin. In Aim 1 we will characterize the mechanism that mediates the phosphate effect on hepatocytes in vitro, and we will study whether phosphate communicates with FGF23/FGFR4 signaling when stimulating IL6 and hepcidin production. Since IL6 is a potent inducer of skeletal muscle atrophy and hepcidin causes functional iron deficiency, we will also determine whether by targeting the liver, elevated serum levels of phosphate and FGF23 contribute to muscle wasting and anemia. To study the contribution of FGF23 in this context, we have generated a novel mouse model with hepatocyte-specific deletion of FGFR4. In Aim 2, we will determine whether following the induction of kidney injury via administration of an adenine-supplemented diet, these mice are protected from increases in hepatic and systemic levels of IL6 and hepcidin, as well as skeletal muscle injury and anemia. In the Col4a3 knockout model of CKD, we will inject a FGFR4-specific blocking antibody to determine if systemic FGFR4 inhibition has similar protective effects, which would suggest a therapeutic potential for anti-FGFR4 in CKD. In our preliminary studies we also found that increasing phosphate concentrations induce FGF23 production in cultured hepatocytes, and that mouse models of CKD as well as mice on high-phosphate diet express FGF23 in the liver, which is not detected in control mice. In Aim 3, we will test whether liver-derived FGF23 is required for the in vivo effects of phosphate. We have generated a novel mouse model for the hepatocyte-specific deletion of FGF23, and after administration of an adenine or high-phosphate diet, we will study if IL6 and hepcidin production are reduced as well as potential protective effects on skeletal muscle and iron metabolism.

项目总结慢性肾脏疾病(CKD)是一种健康流行病，由于各种合并症而增加死亡风险。矿物质代谢的改变是晚期CKD的一个标志，其中高磷血症和血清成纤维细胞生长因子23浓度的相关升高被怀疑是直接导致组织损伤和死亡，但其潜在机制尚不完全清楚。我们先前发现，通过成纤维细胞生长因子受体(FGFR)4靶向心肌细胞，升高的FGF23激活一种 CKD啮齿动物模型中特定的信号通路和诱导的心肌肥厚。我们还报道说，通过激活这一机制后，FGF23可直接靶向肝细胞。然而，FGF23的后果是S 肝脏的作用还没有在体内进行研究。与FGF23相比，人们对直接血磷升高的病理作用。机制研究表明，通过靶向血管平滑肌细胞通过特定的磷酸盐转运体和信号媒介，磷酸盐升高可导致血管钙化。磷酸盐浓度升高对心脏的直接作用尚不清楚，到目前为止，磷酸盐对肝脏的潜在影响还没有得到分析。我们的初步体外研究原代小鼠肝细胞表明磷酸盐和FGF23均可诱导炎性细胞因子，如白介素6(IL6)和海普西丁。在目标1中，我们将描述在体外，我们将研究磷酸盐对肝细胞的作用机制。当刺激IL6和海普西丁的产生时，与FGF23/FGFR4信号传递。由于IL6是一种强大的骨骼肌萎缩诱导剂和海普西丁导致功能性铁缺乏，我们还将确定通过以肝脏为靶点，升高的血清磷酸盐和FGF23水平是否有助于肌肉消瘦和贫血。为了研究FGF23在这方面的贡献，我们产生了一种新的小鼠肝细胞特异性缺失FGFR4的模型。在目标2中，我们将确定是否遵循归纳通过给予腺嘌呤补充的饮食来减少肾脏损伤，这些小鼠受到保护，不受肝脏和全身水平的IL6和海普西丁，以及骨骼肌损伤和贫血。在Col4A3中 CKD的基因敲除模型，我们将注射FGFR4特异性阻断抗体来确定全身性FGFR4 抑制具有相似的保护作用，提示抗FGFR4对CKD有治疗潜力。在……里面我们的初步研究还发现，增加磷酸盐浓度会诱导FGF23在培养肝细胞，CKD小鼠模型和高磷饮食小鼠表达FGF23 在肝脏中，这在对照组小鼠中没有检测到。在目标3中，我们将测试是否需要肝脏来源的FGF23 对于磷酸盐在体内的影响。我们已经建立了一种新的小鼠肝细胞特异性模型 FGF23的缺失，以及用腺嘌呤或高磷饮食后，我们将研究IL6和海普西丁的产生减少，对骨骼肌和铁代谢的潜在保护作用也会减少。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fibroblast growth factor 23, klotho and heparin.

DOI：
10.1097/mnh.0000000000000895
发表时间：
2023-07-01
期刊：
CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION
影响因子：
3.2
作者：
Thomas, S. Madison;Li, Qing;Faul, Christian
通讯作者：
Faul, Christian

Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling.

DOI：
10.7554/elife.74782
发表时间：
2022-03-18
期刊：
eLife
影响因子：
7.7
作者：
Czaya B;Heitman K;Campos I;Yanucil C;Kentrup D;Westbrook D;Gutierrez O;Babitt JL;Jung G;Salusky IB;Hanudel M;Faul C
通讯作者：
Faul C

DACH1 as a multifaceted and potentially druggable susceptibility factor for kidney disease.