# Impact of Phosphaturia on Renal Osteopontin Production and PKD Progression

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2021 · $416,015

## Abstract

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 which 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 and is primarily responsible for this maintenance of phosphate balance by the kidneys. 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 kidney injury, immune cell infiltration, and fibrosis. In preliminary studies, we observed
phosphaturic mouse models to exhibit evidence of early kidney injury and fibrosis. Moreover, additional
experiments revealed dietary phosphate restriction slows PKD progression in several mouse models of cystic
kidney disease.
 The kidney expression of osteopontin (OPN), a matricellular protein that is produced by tubular epithelial
cells and uses an ASARM peptide motif to enhance phosphate solubility in urine, is increased in rodent models
of both phosphaturia and cystic kidney disease. In addition to its function of inhibiting mineral aggregation,
OPN has established functions to stimulate cell proliferation and enhance macrophage recruitment to sites of
injury; thus, kidney OPN production in PKD may contribute to the pathophysiology of cyst formation and
associated pathology.
 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 the proposed experiments to determine: (1) the impact of
high urine phosphate on PKD progression, (2) the role of osteopontin in mediating the effect of high dietary
phosphate on cyst growth, macrophage recruitment and interstitial fibrosis, (3) if administration of a decoy
ASARM peptide can enhance the solubility of tubular phosphate and prevent PKD progression, and (4) the
prevalence, composition, and surrounding pathology of mineral aggregates in human and mouse PKD kidneys.

## Key facts

- **NIH application ID:** 10367190
- **Project number:** 2R01DK122212-03
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Jason Stubbs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $416,015
- **Award type:** 2
- **Project period:** 2021-09-23 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367190

## Citation

> US National Institutes of Health, RePORTER application 10367190, Impact of Phosphaturia on Renal Osteopontin Production and PKD Progression (2R01DK122212-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10367190. Licensed CC0.

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