Abstract: FR-PO173
Atypical Protein Kinase C Zeta Is Indispensable for Calcium Oxalate Crystal Clearance in a Dietary-Induced Mouse Model of Kidney Injury
Session Information
- AKI: Mechanisms
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Messing, Melina, University of California Santa Barbara, Santa Barbara, California, United States
- Holznecht, Nickolas J., University of California Santa Barbara, Santa Barbara, California, United States
- Strubl, Sebastian, Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany
- 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
- Wong, Rachel, University of California Santa Barbara, Santa Barbara, California, United States
- Weimbs, Thomas, University of California Santa Barbara, Santa Barbara, California, United States
Background
Previously, we showed that renal calcium oxalate (CaOx) crystal deposition triggers reversible tubular dilation to expel crystals from normal kidneys and accelerates disease progression in polycystic kidney disease (PKD) rodent models. Given our previous report that atypical protein kinase C zeta (PKCζ) expression is downregulated in patients with autosomal dominant polycystic kidney disease (ADPKD) and that restoration of PKCζ improves the condition, we investigated the role of PKCζ in the kidneys during and after CaOx deposition.
Methods
To explore reversible tubular dilation and signaling activity in PKCζ-knockout (KO) kidneys following CaOx deposition, we administered a 0.67% sodium oxalate (NaOx) diet to P56 male wild-type and PKCζ-KO mice for up to 14 days, followed by a recovery period of up to 28 days after cessation of NaOx treatment.
Results
Both groups demonstrated substantial renal crystal deposition; however, wild-type mice remained healthy throughout the dietary intervention. In contrast, PKCζ-KO mice showed increased susceptibility to injury, leading to mortality around day 10. Further investigation revealed significantly higher crystal accumulation in PKCζ-KO mice compared to wild-type. Notably, reintroduction of a normal diet after 3 days on NaOx allowed for crystal clearance in wild-type mice, but not in PKCζ-KO mice, where crystals persisted. Additionally, PKCζ-KO mice displayed enduring renal damage characterized by significant collagen deposition and inflammation, even after a 28-day washout period.
Conclusion
These findings underscore the critical role of PKCζ in managing CaOx crystal deposition and suggest its potential as a therapeutic target for preventing chronic kidney disease progression following crystal-induced injury.
Funding
- Private Foundation Support