Impact of Phosphaturia on Renal Osteopontin Production and PKD Progression

项目概要/摘要 常染色体显性遗传性多囊肾病（PKD）的特征是大量的 肾囊肿是一种慢性肾功能衰竭的疾病，其发病机制是肾功能衰竭。 疾病（ESRD）。肾小管上皮细胞异常增殖、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， 不确定。 系统性磷酸盐平衡受到严格调节，磷酸盐的肾脏排泄至关重要 以消除饮食中过量的磷酸盐。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著增加以保持磷酸盐平衡。成纤维 生长因子23（FGF 23）是一种诱导尿磷酸盐排泄的循环激素，在早期糖尿病患者中升高， 阶段PKD，并且主要负责通过肾脏维持磷酸盐平衡。较高 膳食磷酸盐消耗和FGF 23升高与肾功能更快下降相关 在慢性肾病（CKD）中，表明尿磷酸盐排泄增加可能有助于 肾功能减退我们认为高浓度的管状磷酸盐具有肾毒性， 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 磷酸尿小鼠模型显示早期肾损伤和纤维化的证据。此外，额外 实验表明，饮食磷酸盐限制减缓了几种囊性增生小鼠模型中PKD的进展。 肾病 骨桥蛋白（OPN）是一种由肾小管上皮细胞产生的基质细胞蛋白， 细胞，并使用ASARM肽基序来提高尿中磷酸盐的溶解度，在啮齿动物模型中增加 磷酸盐尿症和囊性肾病除了抑制矿物质聚集的功能外， 骨桥蛋白具有刺激细胞增殖和增强巨噬细胞募集到肿瘤部位的功能。 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有助于上皮细胞损伤， 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。我们将使用拟议的实验来确定：（1） 高尿磷对PKD进展的影响，（2）骨桥蛋白在介导高饮食影响中的作用 磷酸盐对囊肿生长、巨噬细胞募集和间质纤维化的影响，（3）如果给予诱饵， ASARM肽可以增强肾小管磷酸盐的溶解性并阻止PKD进展，和（4）ASARM肽可以增强肾小管磷酸盐的溶解性并阻止PKD进展。 人类和小鼠PKD肾脏中矿物质聚集体的患病率、组成和周围病理学。

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.