A Novel Driver of Hyperphosphatemia and Vascular Calcification in CKD

高磷血症是心血管并发症的主要原因，如心血管钙化。 慢性肾脏病(CKD)患者。慢性肾脏病通过以下途径引起严重的磷酸盐平衡失衡 甲状旁腺激素(PTH)和成纤维细胞生长因子-23这两个磷酸激素轴的紊乱 (成纤维细胞生长因子23)。甲状旁腺素和成纤维细胞生长因子-23主要通过增加近端的降解来减少磷酸盐的再吸收 小管特异的钠依赖型II型磷酸转运蛋白，NaPi2a。尽管我们知道磷酸盐 动态平衡由涉及骨骼、肠道、肾脏和甲状旁腺的系统反馈环路调节。 腺体，我们认为CKD介导的磷酸盐稳态失调的起始发生在 肾脏。利用序列rna-seq和rNAi文库筛选，我们已经确定了一个新的候选基因。 近端小管对磷酸盐稳态的特异性调节。这个应用程序的中心前提来自我们的 初步结果是：1)一种新的近端小管特异蛋白的调节与物理上相互作用 NaPi2a并通过影响NaPi2a的稳定性影响磷酸盐的重新吸收，2)该基因敲除的小鼠 蛋白质严重破坏了磷酸盐稳态，导致严重的高磷血症和 肾刷状交界膜NaPi2a急剧增加导致血管钙化；3)慢性肾脏病 显著降低肾刷状边界膜中这种蛋白质的水平。这个项目是一个合作项目 心血管疾病生物学专家(宫崎骏，博士科学家)和磷酸盐 运输者(布莱恩，医学博士/博士科学家)。我们将采用一个创新的微观方法小组 和新的小鼠遗传模型来评估新的近端小管特异蛋白在调节中的作用 磷酸盐稳态与CKD介导的高磷血症和血管病变的发病机制 钙化。提出了两个具体目标。目标1将确定近端小管- 特定蛋白调节甲状旁腺素和FGF23对NaPi2a的降解。目标2将研究是否 近曲小管特异蛋白参与CKD介导的高磷血症和心血管疾病 完成度。该项目的完成将为CKD介导的高磷血症提供一个新的靶点 心血管并发症。

Hyperphosphatemia is a major cause of cardiovascular complications such as cardiovascular calcification in patients with chronic kidney disease (CKD). CKD causes a severe imbalance of phosphate homeostasis through the disruption of two phosphaturic hormonal axes, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). PTH and FGF-23 reduce phosphate re-absorption mainly by increasing degradation of a proximal tubule-specific Na-dependent type II phosphate transporter, NaPi2a. Although we understand that phosphate homeostasis is regulated by a systemic feedback loop involving the bone, intestine, kidneys and parathyroid gland, we believe that the initiation of CKD-mediated dysregulation of phosphate homeostasis occurs at the kidney. Using a sequential RNA-seq and RNAi library screening, we have identified a novel candidate for proximal tubule-specific regulation of phosphate homeostasis. The central premise of this application from our preliminary results is that 1) the modulation of a novel proximal tubular-specific protein physically interacts with NaPi2a and affects phosphate re-absorption by affecting NaPi2a stability, 2) the mice with a knockout of this protein developed severe disruption of phosphate homeostasis, resulting in severe hyperphosphatemia and vascular calcification by drastically increasing NaPi2a in the renal brush boarder membrane and 3) CKD significantly reduces levels of this protein in the renal brush boarder membrane. This project is a collaboration between experts with the biology of cardiovascular diseases (Miyazaki, PhD scientist) and phosphate transporters (Blaine, MD/PhD scientist). We will employ an innovative panel of novel microscopic methodologies and novel genetic mouse models to assess the role of the novel proximal tubule-specific protein in the regulation of phosphate homeostasis and the pathogenesis of CKD-mediated hyperphosphatemia and vascular calcification. Two specific aims are proposed. Aim 1 will identify mechanisms by which the proximal tubular- specific protein regulates NaPi2a degradation in response to PTH and FGF23. Aim 2 will examine whether the proximal tubular-specific protein contributes to CKD-mediated hyperphosphatemia and cardiovascular completions. Completion of this project will provide a novel target of CKD-mediated hyperphosphatemia and cardiovascular complications.