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。CKD通过以下途径引起磷酸盐稳态的严重失衡： 两个磷酸尿激素轴，甲状旁腺激素（PTH）和成纤维细胞生长因子-23的破坏 （FGF-23）。PTH和FGF-23减少磷酸盐重吸收主要是通过增加近端 微管特异性钠依赖性II型磷酸盐转运蛋白，NaPi 2a。尽管我们知道磷酸盐 体内平衡是由包括骨骼、肠、肾和甲状旁腺的系统反馈回路调节的 我们认为，CKD介导的磷酸盐稳态失调的起始发生在 肾使用顺序RNA-seq和RNAi文库筛选，我们已经确定了一个新的候选人， 磷酸盐稳态的近端小管特异性调节。本申请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性蛋白的调节与 NaPi 2a并通过影响NaPi 2a稳定性影响磷酸盐重吸收，2）敲除此基因的小鼠 蛋白质严重破坏磷酸盐稳态，导致严重的高磷酸盐血症， 肾刷状缘膜中NaPi 2a急剧增加导致的血管钙化和3）CKD 显着降低肾刷缘膜中该蛋白的水平。这个项目是一个合作 心血管疾病生物学专家（宫崎，博士科学家）和磷酸盐之间 转运蛋白（Blaine，医学博士/博士科学家）。我们将采用一个创新的小组， 和新的遗传小鼠模型，以评估新的近端小管特异性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性高磷血症的发病机制 钙化提出了两个具体目标。目的1将确定近端肾小管- 特异性蛋白质响应于PTH和FGF 23调节NaPi 2a降解。目标2将审查 近端小管特异性蛋白有助于CKD介导的高磷血症和心血管疾病 完成。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.