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，并经常在终末期肾功能达到顶峰。 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。 分期PKD。高膳食磷酸盐摄入量和FGF23升高都与更快的 慢性肾脏病(CKD)患者肾功能下降，表明尿磷排泄增加 可能会导致肾功能的下降。我们认为高浓度的管状磷酸盐 是肾毒性的，导致进行性肾脏损伤、免疫细胞渗透和纤维化。在初步研究中， 我们观察到两种磷酸尿症小鼠模型(NaPi2a-/-和Hyp小鼠)表现出肾脏基因的增加 早期肾损伤和纤维化标志物的表达。此外，更多的实验揭示了饮食 限制磷酸盐以减缓pcy/pcy小鼠的PKD进展。 骨桥蛋白(OPN)，一种利用ASARM多肽基序增强磷酸盐的基质细胞蛋白 肾小管上皮细胞增加尿液中的溶解度。OPN已经建立了刺激功能 细胞增殖和促进巨噬细胞募集到细胞损伤部位；因此，肾脏OPN的产生 PKD可能参与了囊性肾病的病理生理过程。 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。我们将使用细胞培养和小鼠研究来确定：(1) 高尿磷酸盐对PKD进展的影响，(2)骨桥蛋白在囊上皮细胞中的作用 增殖、巨噬细胞募集和间质纤维化，以及(3)如果给予ASARM肽 能提高管状磷酸盐的溶解度，防止PKD进展。

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, and 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. 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 renal injury, immune cell infiltration, and fibrosis. In preliminary studies, we observed two phosphaturic mouse models (NaPi2a-/- and Hyp mice) to exhibit increased renal gene expression for markers of early kidney injury and fibrosis. Moreover, additional experiments revealed dietary phosphate restriction to slow PKD progression in pcy/pcy mice. Osteopontin (OPN), a matricellular protein that uses an ASARM peptide motif to enhance phosphate solubility in urine, is increased by tubular epithelial cells in PKD. OPN has established functions to stimulate cell proliferation and enhance macrophage recruitment to sites of cellular injury; thus, renal OPN production in PKD may contribute to the pathophysiology of cystic kidney disease. 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 cell culture and mouse studies to determine: (1) the impact of high urine phosphate on PKD progression, (2) the role of osteopontin in cyst epithelial cell proliferation, macrophage recruitment and interstitial fibrosis, and (3) if administration of an ASARM peptide can enhance the solubility of tubular phosphate and prevent PKD progression.