# Role of renal crystal deposition in the progression of polycystic kidney disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2020 · $345,375

## Abstract

Project Summary/Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is a very common, inherited disease affecting the
world's population with a frequency of approximately 1:500. No approved treatment to slow or halt disease
progression is currently available in the US. The disease progresses slowly to renal failure, typically in the
4-6th decades of life. However, for unknown reasons the rate of progression greatly varies from patient to
patient even within the same family suggesting that environmental factors may affect disease progression.
Recent results from animal studies suggest that renal insults are required - in addition to the gene mutation -
for renal cysts to arise. However, rare forms of renal injury are unlikely to account for the constant pace of
disease progression in humans.
 Our results suggest that a much more prevalent form of sub-clinical renal insult is the trigger of renal cyst
formation that determines the rate of progression in ADPKD: microcrystals that are sporadically lodged in renal
tubule lumens. We show that deposition of calcium oxalate (CaOx) crystals in renal tubules leads to rapid
activation of the mTOR and Src/STAT3 signaling pathways, both of which are also strongly activated in
ADPKD. In addition, CaOx crystal deposition leads to rapid tubule diameter widening that can be blocked by
mTOR inhibition. Our results suggest that tubule dilation is a purposeful, and previously unrecognized,
protective mechanism that facilitates crystal excretion. After crystal clearance, tubule diameters return to
normal within a week. However, in mice lacking PC1 - the protein affected in ADPKD - CaOx challenge leads to
persistent tubule dilation that “overshoots” to cystic progression. This suggests that PC1 is required to re-
establish normal tubule diameters after insults. We hypothesize (1) that tubule dilation is an innate renal
protective mechanism against tubular crystals; and (2) that this mechanism inadvertently acts as a trigger for
tubule dilation leading to cyst formation in ADPKD. If correct - these findings immediately open a new and
highly feasible avenue for therapeutic intervention because well-established treatments for recurring
nephrolithiasis (dietary changes, increased water intake, citrate) should also be effective in slowing the
progression of ADPKD.
 Using mouse and rat models of CaOx nephrolithiasis we will investigate tubule dilation and signaling
pathway activation in response to crystal deposition and test whether citrate treatment prevents these effects
(Aim 1). Using pharmacological inhibitors and genetic mouse models we will determine if tubule dilation is
required for effective crystal clearance (Aim 2). Using conditional knockout mice for the ablation of cilia or PC1,
respectively, we will determine if tubular crystal deposition acts as a trigger for cystogenesis (Aim 3). Using a
mosaic PC1-KO mouse model and a rat model of PKD we will determine if crystal burden modulates disease
severity ...

## Key facts

- **NIH application ID:** 9846223
- **Project number:** 5R01DK109563-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** Thomas Weimbs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,375
- **Award type:** 5
- **Project period:** 2017-01-16 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846223

## Citation

> US National Institutes of Health, RePORTER application 9846223, Role of renal crystal deposition in the progression of polycystic kidney disease (5R01DK109563-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9846223. Licensed CC0.

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