# Decoding reno-protective mechanisms in mouse Pkhd1 models: Implications for ARPKD therapeutics

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2021 · $392,700

## Abstract

PROJECT SUMMARY
There are ~1,500 patients in the United States with autosomal recessive polycystic kidney disease (ARPKD;
MIM 173900), a hepatorenal fibrocystic disorder characterized by enlarged kidneys with innumerable collecting
duct cysts and progressive loss of renal function. Essentially all cases of ARPKD can be attributed to mutations
in PKHD1, which encodes a single-pass transmembrane protein, fibrocystin/polyductin (FPC). We currently have
very little insight into the pathogenesis of human ARPKD and thus, treatment is largely supportive.
Striking species-specific differences in the PKHD1/Pkhd1 renal phenotype may offer important insights into
disease mechanisms. While human patients with either missense or truncating PKHD1 mutations have severe
renal cystic disease, mouse Pkhd1 models with engineered truncating mutations (and presumably loss of FPC
function) express minimal or no renal disease. Our preliminary studies reveal that while MYC is overexpressed
in human ARPKD kidneys, Myc is not overexpressed in mouse Pkhd1 kidneys. In previous studies, we have
shown that FPC undergoes Notch-like processing with cleavage of the carboxy terminus (FPC-CTD) from the
plasma membrane and nuclear trafficking. Here, we demonstrate that the mouse FPC-CTD binds directly to the
Myc P1 promoter and increases Myc expression.
Based on these findings, we hypothesize that mouse renal epithelia can compensate for the loss of FPC-CTD
function through reno-protective mechanisms and that species-specific, FPC-CTD regulation of Myc expression
is central to this reno-protection. We speculate that while these mechanisms are not normally operative in human
renal epithelia, they may identify new opportunities for therapeutic targeting in human ARPKD renal disease. We
propose two specific aims to test our hypothesis: (1) define how the FPC-CTD regulates Myc/MYC expression
in mouse and human renal epithelia and determine whether disruption of the proposed regulatory circuits is a
central driver of renal cystogenesis; and (2) compare the FPC-CTD nuclear interactome in mouse and human
renal epithelia and test whether differences in transcriptional targets identifies reno-protective pathways in mouse
kidneys.
Our studies will advance the field by sequentially addressing the transcriptional role of FPC-CTD. Specifically,
we will: 1) determine
mouse Pkhd1 models;
how FPC-CTD related Myc transcriptional regulation contributes to reno-protection in
and 2) identify putative mechanisms that allow mouse renal epithelia to compensate for
the loss of FPC-CTD nuclear function. Moving forward, these data will lay the foundation for translating mouse
reno-protective mechanisms into novel, therapeutic strategies that attenuate human PKHD1-related renal cystic
disease.

## Key facts

- **NIH application ID:** 10170340
- **Project number:** 5R01DK121530-02
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** LISA MARIE GUAY-WOODFORD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $392,700
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170340

## Citation

> US National Institutes of Health, RePORTER application 10170340, Decoding reno-protective mechanisms in mouse Pkhd1 models: Implications for ARPKD therapeutics (5R01DK121530-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10170340. Licensed CC0.

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