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：
10033790
负责人：
Christian Faul
金额：
$ 37.49万
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/10033790
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 Control Animal Diet Drug Targeting Enzyme-Linked Immunosorbent Assay Epidemic FGFR1 gene FGFR4 gene Fibroblast Growth Factor Receptors Health Heart Heart Hypertrophy Hepatic Hepatocyte Hormones In Vitro Inflammation Inflammatory Injections Injury to Kidney Inorganic Phosphate Transporter Integral Membrane Protein Interleukin-6 Kidney Knock-out Link Liver Mediating Mediator of activation protein Metabolism Minerals Mitogen-Activated Protein Kinases Modeling Molecular Mus Muscular Atrophy PTH gene Pathologic Pathology Patients Pharmacology Phospholipase Physiological Production Protein Isoforms Reporting Research Proposals Rodent Model Serum Severity of illness 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/antagonist inorganic phosphate iron deficiency iron metabolism knock-down mortality mortality risk mouse model muscle strength novel novel therapeutics nuclear factors of activated T-cells paracrine premature prevent protective effect protein function receptor release factor skeletal muscle metabolism skeletal muscle wasting 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.

项目摘要慢性肾脏疾病（CKD）是一种健康流行病，可增加由于各种合并症而导致死亡的风险。矿物质代谢的改变是晚期CKD的标志，在该标志血清浓度的成纤维细胞生长因子（FGF）23的相关升高被怀疑是直接有助于组织损伤和死亡率，但尚不完全了解潜在的机制。我们以前发现，通过通过FGF受体（FGFR）4靶向心肌细胞，FGF23升高会激活A 特定的信号通路并诱导CKD啮齿动物模型中的心脏肥大。我们还报告了激活这种机制，FGF23可以直接靶向肝细胞。但是，FGF23的后果肝作用尚未在体内进行调查。与FGF23相比，关于直接的知之甚少血清磷酸盐升高的病理作用。机械研究表明，通过靶向血管平滑肌细胞通过特定的磷酸转运蛋白和信号介导子，磷酸盐升高会导致血管计算。尚不了解升高磷酸盐浓度在心脏上的直接作用，到目前为止，尚未分析磷酸盐对肝脏的潜在影响。我们的初步体外研究原代小鼠肝细胞表明磷酸盐和FGF23都可以诱导炎性细胞因子，例如白介素6（IL6）和肝素。在AIM 1中，我们将表征在体外介导磷酸对肝细胞的作用的机制，我们将研究磷酸盐是否是否当刺激IL6和肝素产生时，与FGF23/FGFR4信号传导通信。由于IL6是一个骨骼肌萎缩和肝素的有效诱导剂会导致功能性铁缺乏症，我们也将确定是否通过靶向肝脏，磷酸盐和FGF23的血清水平升高有助于肌肉浪费和贫血。为了研究FGF23在这种情况下的贡献，我们已经产生了一种新的鼠标具有FGFR4的肝细胞特异性缺失的模型。在AIM 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肾脏损伤，这些小鼠受到保护 IL6和肝素的肝和全身水平，以及骨骼肌损伤和贫血。在Col4a3中 CKD的敲除模型，我们将注入FGFR4特异性阻断抗体，以确定是否是全身FGFR4 抑制作用具有相似的保护作用，这表明CKD中抗FGFR4具有治疗潜力。我们的初步研究还发现，磷酸盐浓度的升高会影响FGF23的产生培养的肝细胞，CKD的小鼠模型以及高磷酸饮食的小鼠Express FGF23 在AIM 3中，我们将测试是否需要肝脏衍生的FGF23 用于磷酸盐的体内作用。我们为肝细胞特异性生成了一种新型的鼠标模型删除FGF23，在给药后，我们将研究IL6和肝素的产生减少以及对骨骼肌和铁代谢的潜在保护作用。