Impact of Phosphaturia on Renal Osteopontin Production and PKD Progression

磷酸盐尿对肾骨桥蛋白产生和 PKD 进展的影响

基本信息

批准号：
10367190
负责人：
Jason Stubbs
金额：
$ 41.6万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367190
关键词：
Acceleration Affect Attenuated Autosomal Dominant Polycystic Kidney Binding Cell Culture Techniques Cell Proliferation Cells Chronic Chronic Kidney Failure Consumption Crystal Formation Crystallization Cyst Cystic Kidney Diseases Cystic kidney Data Deposition Dietary Intervention Dietary intake Disease Disease Progression End stage renal failure Epithelial Cell Proliferation Epithelial Cells Epithelial cyst Equilibrium Event Excretory function Exhibits FRAP1 gene Fibrosis Functional disorder Generations Genetic Growth Hormones Human Immune In Vitro Infiltration Ingestion Injury Injury to Kidney Integrin Binding Integrin alphaV Integrins Kidney Kidney Diseases Lead Liquid substance Location Maintenance Mediating Metabolism Methods Minerals Mus Nephrons Oral Pathologic Pathology Pathway interactions Peptides Pharmacology Polycystic Kidney Diseases Prevalence Production Proteins RGD (sequence)Renal function Residual state Rodent Rodent Model Role Signal Transduction Site Solubility Testing Tissues Translations Tubular formation Urine calcium phosphate cell injury clinical practice dietary dietary excess experimental study fibroblast growth factor 23 improved inhibitor/antagonist inorganic phosphate integrin-linked kinase interstitial kidney fibrosis macrophage mouse model nanocrystal nephrotoxicity novel novel therapeutic intervention osteopontin preservation prevent recruit sodium-phosphate cotransporter proteins theories urinary

项目摘要

PROJECT SUMMARY/ABSTRACT Autosomal dominant polycystic kidney disease (PKD) is characterized by the accumulation of numerous renal cysts leading to a progressive decline in kidney function which frequently culminates in end-stage renal disease (ESRD). Aberrant tubular epithelial cell proliferation, macrophage infiltration, and tubulointerstitial fibrosis are important contributors to PKD progression; however, factors promoting these events remain undetermined. Systemic phosphate balance is tightly regulated, with renal excretion of phosphate being critically important for the elimination of excess dietary phosphate. When functional nephron numbers are reduced, as in PKD, phosphate excretion by residual nephrons is dramatically increased to preserve phosphate balance. Fibroblast growth factor 23 (FGF23), a circulating hormone that induces urinary phosphate excretion, is elevated in early- stage PKD and is primarily responsible for this maintenance of phosphate balance by the kidneys. Both high dietary phosphate consumption and elevated FGF23 are associated with a more rapid decline in renal function in chronic kidney disease (CKD), indicating that increased urinary phosphate excretion may contribute to decrements in kidney function. We propose that high concentrations of tubular phosphate are nephrotoxic, leading to progressive kidney injury, immune cell infiltration, and fibrosis. In preliminary studies, we observed phosphaturic mouse models to exhibit evidence of early kidney injury and fibrosis. Moreover, additional experiments revealed dietary phosphate restriction slows PKD progression in several mouse models of cystic kidney disease. The kidney expression of osteopontin (OPN), a matricellular protein that is produced by tubular epithelial cells and uses an ASARM peptide motif to enhance phosphate solubility in urine, is increased in rodent models of both phosphaturia and cystic kidney disease. In addition to its function of inhibiting mineral aggregation, OPN has established functions to stimulate cell proliferation and enhance macrophage recruitment to sites of injury; thus, kidney OPN production in PKD may contribute to the pathophysiology of cyst formation and associated pathology. We hypothesize that high concentrations of tubular phosphate in PKD contribute to epithelial cell injury and OPN production, which together promote cyst epithelial cell proliferation and macrophage recruitment that accelerate kidney disease progression. We will use the proposed experiments to determine: (1) the impact of high urine phosphate on PKD progression, (2) the role of osteopontin in mediating the effect of high dietary phosphate on cyst growth, macrophage recruitment and interstitial fibrosis, (3) if administration of a decoy ASARM peptide can enhance the solubility of tubular phosphate and prevent PKD progression, and (4) the prevalence, composition, and surrounding pathology of mineral aggregates in human and mouse PKD kidneys.

项目概要/摘要常染色体显性多囊肾病 (PKD) 的特点是大量细胞的积累肾囊肿导致肾功能进行性下降，常常导致终末期肾病疾病（终末期肾病）。异常的肾小管上皮细胞增殖、巨噬细胞浸润和肾小管间质纤维化是 PKD 进展的重要因素；然而，促进这些事件的因素仍然存在未确定。全身磷酸盐平衡受到严格调节，肾脏排泄磷酸盐至关重要用于消除膳食中过量的磷酸盐。当功能性肾单位数量减少时，如 PKD，残余肾单位的磷酸盐排泄显着增加，以保持磷酸盐平衡。成纤维细胞生长因子 23 (FGF23) 是一种诱导尿磷酸盐排泄的循环激素，在早期阶段会升高。 PKD 阶段，主要负责肾脏维持磷酸盐平衡。都高膳食磷酸盐消耗和 FGF23 升高与肾功能更快下降有关在慢性肾脏病（CKD）中，表明尿磷酸盐排泄增加可能有助于肾功能下降。我们认为高浓度的肾小管磷酸盐具有肾毒性，导致进行性肾损伤、免疫细胞浸润和纤维化。在初步研究中，我们观察到磷酸盐小鼠模型显示早期肾损伤和纤维化的证据。此外，额外的实验表明，在几种囊性囊肿小鼠模型中，膳食磷酸盐限制可减缓 PKD 的进展肾脏疾病。骨桥蛋白 (OPN) 的肾脏表达，骨桥蛋白是一种由肾小管上皮产生的基质细胞蛋白细胞并使用 ASARM 肽基序来增强尿液中磷酸盐的溶解度，在啮齿动物模型中增加磷酸盐尿和囊性肾病。除了具有抑制矿物质聚集的功能外， OPN 具有刺激细胞增殖和增强巨噬细胞募集至细胞位点的功能受伤;因此，PKD 中肾脏 OPN 的产生可能有助于囊肿形成的病理生理学，相关病理学。我们假设 PKD 中高浓度的肾小管磷酸盐会导致上皮细胞损伤， OPN 的产生，共同促进囊肿上皮细胞增殖和巨噬细胞募集，加速肾脏疾病的进展。我们将使用所提出的实验来确定：（1）高尿磷酸盐对 PKD 进展的影响，（2）骨桥蛋白在介导高饮食作用中的作用磷酸盐对囊肿生长、巨噬细胞募集和间质纤维化的影响，(3) 如果施用诱饵 ASARM 肽可以增强肾小管磷酸盐的溶解度并防止 PKD 进展，并且 (4) 人类和小鼠 PKD 肾脏中矿物聚集体的患病率、组成和周围病理学。