# Polycystin Dependent Mechanisms of Tubular Plasticity

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $473,605

## Abstract

Autosomal dominant polycystic kidney disease (ADPKD) results primarily from mutations in PKD1 and PKD2
encoding polcysytin-1 (PC1) and polycystin-2 (PC2), respectively. Since PKD1 and PKD2 were discovered, there
has been significant progress in understanding the functions of the polycystins (PCs). Much recent progress has
been based on in vivo orthologous gene mouse models which in turn most often rely on controlled inactivation
of Pkd1 or Pkd2 using the Cre-loxP system. Our past work has extended beyond Cre-loxP to include modified
bacterial artificial chromosome transgenics as well as a model in which second-hit inactivation occurs by a
stochastic, Cre recombinase-independent process (Pkd2WS25). While loss of function models offer valuable
information, we sought to determine whether ADPKD is actually reversible following Pkd gene reactivation, and
if so, at what point in the course of ADPKD is reversal still possible. We developed mouse models that use adult
inducible Cre–loxP for the initial Pkd gene inactivation and a separately inducible Flp–FRT system for
subsequent reactivation of the same Pkd gene to address these questions. Applying this system to Pkd2, we
found that cyst formation is rapidly reversible and that dilated cysts lined by proliferating, squamoid epithelial
cells rapidly revert to non-proliferating columnar epithelia with normal appearing nephron lumens, accompanied
by markedly decreased total kidney volume and preservation of kidney function. We will now determine the
extent to which ADPKD is reversible by extending these studies to Pkd1 inactivation/reactivation and to the
Pkd2WS25 mouse which does not require Cre and develops liver cysts as well. We will determine whether there
is a minimum fraction of cyst cells that need to be targeted by reactivation to reverse ADPKD and determine the
latest disease stage at which ADPKD retains reversibility. We will investigate cellular and molecular alterations
operational during resolution of cysts including cell lineage analyses to trace the fates of specific cell types during
the repair process, assess alterations in autophagic flux following PC re-expression as a possible modality for
the changes in cell shape, and determine whether inflammation and fibrosis reverse with Pkd re-expression. We
will attempt to model ADPKD repair in a cell culture-based system. Finally, we will determine the dynamic
changes in transcriptionally defined in vivo cell populations during polycystin re-expression and reversal of
ADPKD using single cell RNA sequencing (scRNA-seq). This will define the plasticity of the cell populations and
the dynamic PC2-expression-dependent changes in transcriptional profiles leading to reversion from the cystic
to a more normal nephron state. The reproducible and rapid initial time course of resolution of cysts affords a
unique opportunity to monitor transitions within and between cell types in near real time and define on the scale
of days the changes that are controll...

## Key facts

- **NIH application ID:** 10003231
- **Project number:** 5R01DK121948-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** STEFAN SOMLO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $473,605
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003231

## Citation

> US National Institutes of Health, RePORTER application 10003231, Polycystin Dependent Mechanisms of Tubular Plasticity (5R01DK121948-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10003231. Licensed CC0.

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