Impact of Phosphaturia on Renal Osteopontin Production and PKD Progression

项目摘要/摘要 常染色体显性遗传性多囊肾病(PKD)的特点是大量的 肾囊肿导致肾功能进行性下降，常常导致终末期肾功能下降。 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 未定。 全身磷酸盐平衡受到严格调节，肾脏磷酸盐排泄至关重要。 用于消除饮食中过量的磷酸盐。当功能性肾单位数量减少时，如在PKD中， 残留肾单位的磷酸盐排泄量显著增加，以维持磷酸盐平衡。成纤维细胞 生长因子23(FGF23)是一种可诱导尿磷排泄的循环激素，在慢性阻塞性肺疾病早期升高。 PKD阶段，主要负责维持肾脏的磷酸盐平衡。都很高 膳食磷酸盐摄入量和FGF23升高与肾功能下降更快相关 在慢性肾脏疾病(CKD)中，表明尿磷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对肾脏有毒性， 导致进行性肾脏损伤、免疫细胞渗入和纤维化。在初步研究中，我们观察到 磷酸尿症小鼠模型显示早期肾脏损伤和纤维化的证据。此外，还增加了 实验表明，限制饮食磷可以减缓几种囊性痴呆小鼠的PKD进展 肾脏疾病。 肾小管上皮细胞产生的基质细胞蛋白骨桥蛋白在肾脏中的表达 在啮齿动物模型中，使用ASARM多肽基序来增加尿中磷酸盐的溶解度是增加的 既有磷酸尿症又有囊性肾病。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促进巨噬细胞向肿瘤部位募集的功能。 因此，PKD时肾脏OPN的产生可能参与了囊性病变的病理生理学过程。 相关病理学。 我们假设PKD中高浓度的小管磷酸盐参与了上皮细胞的损伤和 OPN的产生，共同促进囊上皮细胞增殖和巨噬细胞募集，从而 加速肾脏疾病的进展。我们将使用拟议的实验来确定：(1) 高尿磷酸盐对PKD进展的影响；(2)骨桥蛋白在高脂饮食中的作用 磷酸盐对包囊生长、巨噬细胞募集和间质纤维化的影响，(3)如果使用诱饵 ASARM多肽能增加肾小管磷酸盐的溶解度，阻止PKD进展，(4) 人和小鼠PKD肾脏中矿物聚集体的患病率、组成和周围病理。

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.