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

• 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
• 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

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.

项目摘要/摘要 常染色体显性多囊性肾脏疾病（PKD）的特征是众多 肾脏囊肿导致肾功能逐渐下降，这经常在末期肾脏中 疾病（ESRD）。肾小管上皮细胞的增殖，巨噬细胞浸润和微管间隙 纤维化是PKD进展的重要因素。但是，促进这些事件的因素仍然存在 不确定。 全身性磷酸盐平衡受到严格调节，肾脏排泄磷酸盐至关重要 消除过量的饮食磷酸盐。当功能性肾单位数减少时，如PKD一样 残留肾脏的磷酸盐排泄大大增加以保持磷酸盐的平衡。成纤维细胞 生长因子23（FGF23）是一种诱导尿磷酸排泄的循环激素，早期升高 PKD阶段，主要负责肾脏维持磷酸盐的平衡。两者高 饮食中的磷酸盐消耗和升高的FGF23与肾功能更快下降有关 在慢性肾脏疾病（CKD）中，表明尿磷酸盐排泄增加可能有助于 肾功能下降。我们建议高浓度的管状磷酸盐是肾毒性的， 导致进行性肾脏损伤，免疫细胞浸润和纤维化。在初步研究中，我们观察到 磷小鼠模型以表现出早期肾脏损伤和纤维化的证据。而且，附加 实验表明，在几种囊性小鼠模型中，饮食中的磷酸盐限制减慢了PKD的进展 肾脏疾病。 骨桥蛋白（OPN）的肾脏表达，这是一种由管状上皮产生的母细胞蛋白 细胞并使用Asarm肽基序来增强尿液中的磷酸盐溶解度，在啮齿动物模型中增加 磷酸和囊性肾脏疾病。除了抑制矿物聚集的功能外， OPN已经建立了刺激细胞增殖并增强巨噬细胞募集到地点的功能 受伤;因此，PKD中的肾脏OPN产生可能有助于囊肿形成和 相关病理。 我们假设PKD中高浓度的管状磷酸盐有助于上皮细胞损伤和 OPN产生，共同促进囊肿上皮细胞增殖和巨噬细胞募集 加速肾脏疾病进展。我们将使用拟议的实验来确定：（1） 高尿磷酸对PKD进展，（2）骨桥蛋白在介导高饮食的作用中的作用 磷酸盐的囊肿生长，巨噬细胞募集和间质纤维化，（3）如果给药 ASARM肽可以增强管状磷酸盐的溶解度并防止PKD进展，（4） 人和小鼠PKD肾脏中矿物聚集体的患病率，组成和周围的病理。