# Role of complement in injury-induced cystogenesis among carriers of a single ADPKD gene defect

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2024 · —

## Abstract

PROJECT SUMMARY/ABSTRACT
Renal cysts are the hallmark of autosomal dominant polycystic kidney disease (ADPKD; the fourth major
cause of end-stage kidney disease). The current paradigm of the disease pathogenesis is based on
progressive growth of renal cysts over the life of an ADPKD patient, with the most prominent cysts being
those that emerged in utero. Data obtained with our new image analysis tools, new animal model, and
ADPKD patients show instead that individual cysts' growth rates are highly variable and change over time.
In fact, the proportion of growing cysts is nearly matched by those that are regressing, and an index that
quantifies this growing and regressing cyst phenotype predicts better renal outcomes than total kidney
volume (TKV; an FDA-approved ADPKD biomarker). The use of this new individual cyst-based biomarker
in future studies is likely to transform ADPKD classification and staging to achieve earlier and more accurate
identification of high-risk patients with ADPKD, including children (who have relatively small TKVs).
However, fundamental questions for understanding disease pathobiology and developing new ADPKD
therapeutics remain unanswered. For example, why do some cysts grow faster than others, and why do
some disappear? Since these questions cannot be answered in mouse models (they require two affected
PKD gene alleles to develop cysts and their cysts appear to grow progressively over time without
regression), we propose to study these concepts in our new Pkd2K874A*1/+ rat that develops the growing and
regressing cysts as a heterozygote (like humans). However, since the cyst growth rates are variable and
change over longer time intervals, we propose to use acute kidney injury (AKI) as a model for the initial
dynamic phase of individual cyst growth and the later phase of cyst regression. Since complement C3 is
one of few factors that modulate AKI and cystogenesis and were associated with the rate of human ADPKD
progression, our central hypothesis is that C3 regulates the injury-induced dynamic growth phase of
individual cyst growth in carriers of pathogenic ADPKD gene variants. We will address this central
hypothesis in two Aims: Aim 1. Test the hypothesis that the injury-induced dynamic growth phase of most
renal cysts in heterozygous carriers of the Pkd2 gene defect is mediated by C3 activity - by testing the
effects of ischemia-reperfusion injury (IRI) in animals generated from crosses of the available Pkd2K874A*1/+
and C3 knockout rats. We will complement our advanced MRI imaging techniques (allowing individual renal
cyst monitoring through their co-registration over time) with a single cell and spatial transcriptomics to reveal
which cells and pathways define the dynamic vs. regression phase of individual cyst growth, and how they
are affected by C3 deficiency. Aim 2 will replicate Aim 1 in the already available Pkd1 knockout rat model
(PKD1 and PKD2 genes are the two major ADPKD genes and their protein products for...

## Key facts

- **NIH application ID:** 10805685
- **Project number:** 1I01BX006266-01A1
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Michal Mrug
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805685

## Citation

> US National Institutes of Health, RePORTER application 10805685, Role of complement in injury-induced cystogenesis among carriers of a single ADPKD gene defect (1I01BX006266-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10805685. Licensed CC0.

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