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.

项目概要慢性肾病 (CKD) 是一种健康流行病，会因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，其中高磷血症和成纤维细胞生长因子 (FGF) 23 血清浓度的相关增加被怀疑与直接导致组织损伤和死亡，但我们尚未完全了解其潜在机制。先前发现，通过 FGF 受体 (FGFR) 4 靶向心肌细胞，升高的 FGF23 会激活我们还报道了 CKD 啮齿动物模型中的特定信号通路并诱导心脏肥大。激活这一机制，FGF23可以直接靶向肝细胞。然而，FGF23的后果。与 FGF23 相比，尚未对肝脏作用进行体内研究，对其直接作用知之甚少。血清磷酸盐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蛋白和信号介质，磷酸盐升高会导致血管钙化对心脏的磷酸盐浓度升高的直接作用尚不清楚，到目前为止，我们尚未分析磷酸盐对肝脏的潜在影响。原代小鼠肝细胞表明磷酸盐和 FGF23 均可诱导在目标 1 中，我们将描述炎症细胞因子，例如白细胞介素 6 (IL6) 和铁调素。介导磷酸盐对体外肝细胞作用的机制，我们将研究磷酸盐是否当刺激 IL6 和铁调素产生时，与 FGF23/FGFR4 信号传导进行通信，因为 IL6 是一种骨骼肌萎缩的强效诱导剂和铁调素会导致功能性缺铁，我们还将确定通过靶向肝脏，磷酸盐和 FGF23 的血清水平升高是否有助于肌肉为了研究 FGF23 在这方面的贡献，我们培育了一种新型小鼠。在目标 2 中，我们将确定是否遵循诱导。通过给予腺嘌呤补充饮食来减轻肾损伤，这些小鼠可以免受肾损伤的增加 IL6 和铁调素的肝脏和全身水平，以及 Col4a3 中的骨骼肌损伤和贫血。我们将注射 FGFR4 特异性敲除抗体以确定系统性 FGFR4 是否抑制具有类似的保护作用，这表明抗 FGFR4 在 CKD 中具有治疗潜力。我们的初步研究还发现，增加磷酸盐浓度会诱导 FGF23 的产生培养的肝细胞，CKD 小鼠模型以及高磷酸盐饮食的小鼠表达 FGF23 在目标 3 中，我们将测试是否需要肝脏来源的 FGF23。为了研究磷酸盐的体内作用，我们建立了一种针对肝细胞特异性的新型小鼠模型。删除 FGF23，并在给予腺嘌呤或高磷酸盐饮食后，我们将研究 IL6 和铁调素的产生减少以及对骨骼肌和铁代谢的潜在保护作用。