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 ?ndings 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 in PKD.

Public Health Relevance

Autosomal-dominant polycystic kidney disease (ADPKD) is a very common, inherited disease that leads to kidney failure and can currently not be adequately treated. Our results indicate that microscopic crystals, that normally form in kidneys every day, can trigger the onset and accelerate the progression of ADPKD. If correct - these ?ndings immediately open a new and highly feasible avenue for therapeutic intervention because well- established treatments to prevent crystal growth (dietary changes, increased water intake, citrate) should also be effective in slowing the progression of ADPKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK109563-03
Application #
9648156
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Maric-Bilkan, Christine
Project Start
2017-01-16
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Santa Barbara
Department
Miscellaneous
Type
Organized Research Units
DUNS #
094878394
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106