Abstract: FR-PO242
Uric Acid Crystal Deposition Triggers Tubule Dilation in Normal Kidneys and Cystogenesis in Polycystic Kidney Disease (PKD)
Session Information
- Genetic Diseases of the Kidneys: Cystic - II
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1101 Genetic Diseases of the Kidneys: Cystic
Authors
- Strubl, Sebastian, University of California Santa Barbara, Santa Barbara, California, United States
- Holznecht, Nickolas J., University of California Santa Barbara, Santa Barbara, California, United States
- Torres, Jacob A., University of California Santa Barbara, Santa Barbara, California, United States
- Aceves, Brina A., University of California Santa Barbara, Santa Barbara, California, United States
- Schimmel, Margaret, University of California Santa Barbara, Santa Barbara, California, United States
- Asplund, David Allan, University of California Santa Barbara, Santa Barbara, California, United States
- Kroes, Bradley Christian, University of California Santa Barbara, Santa Barbara, California, United States
- Arjune, Sita, Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
- Mueller, Roman-Ulrich, Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
- Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Weimbs, Thomas, University of California Santa Barbara, Santa Barbara, California, United States
Background
We have previously reported that renal CaOx crystals are commonly cleared from normal kidneys by reversible tubule dilation but can accelerate disease progression in a PKD rat model. Since ADPKD patients also have a high risk for uric acid (UA) crystal deposition we investigated the impact of UA crystals on PKD disease progression in animal models.
Methods
To investigate reversible tubule dilation and signaling activity in normal kidneys upon UA crystal deposition we treated wild-type Sprague Dawley rats with a diet supplemented with uric acid and the uricase inhibitor oxonic acid. To investigate the impact of UA crystal deposition on PKD disease progression we used the same dietary treatment in the HanSPRD model and in heterozygous Pkd1+/- rats.
Results
We report that, in normal kidneys, renal UA crystals lead to reversible tubule dilation and subsequent crystal clearance similar to CaOx crystals. We observed similar activation of the mTOR and Stat3 pathways in dilated renal tubules as described previously. UA crystal deposition accelerated ADPKD disease progression and fibrosis in the HanSPRD model. Furthermore, UA crystal deposition induced cystogenesis in a novel heterozygous Pkd1 rat model.
Conclusion
These results indicate that reversible tubule dilation as a renoprotective clearance mechanism applies to multiple crystal types including UA crystals. For the first time, we show that renal crystals can not only accelerate PKD disease progression but even induce de-novo cystogenesis in an orthologous, heterozygous PKD1+/- model. The latter result suggests that a second-hit somatic mutation is not necessary for cystogenesis. Rather, a heterozygous germline mutation in one PKD1 allele combined with a renal insult by tubular micro-crystals is sufficient to induce cystogenesis. These results have significant implications for the clinical management of individuals with ADPKD.
Funding
- NIDDK Support