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

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.