# A Novel Driver of Hyperphosphatemia and Vascular Calcification in CKD

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $488,632

## Abstract

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.

## Key facts

- **NIH application ID:** 10546434
- **Project number:** 5R01DK124901-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** JUDITH T., BLAINE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $488,632
- **Award type:** 5
- **Project period:** 2020-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10546434

## Citation

> US National Institutes of Health, RePORTER application 10546434, A Novel Driver of Hyperphosphatemia and Vascular Calcification in CKD (5R01DK124901-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10546434. Licensed CC0.

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