Atypical Protein Kinase C Zeta Is Indispensable for Calcium Oxalate Crystal Clearance in a Dietary-Induced Mouse Model of Kidney Injury

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 that atypical protein kinase C zeta (PKCζ) expression is downregulated in patients with autosomal dominant polycystic kidney disease (ADPKD) and that restoration of PKCζ has been shown to improve 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. PKCζ-KO mice exhibited significantly higher crystal accumulation compared to wild-type and inability to excrete these crystals. The failure of PKCζ-KO mice to eliminate CaOx crystals appears to involve underlying mitochondrial dysfunction in PKCζ-deficient renal epithelial cells, with reduced TOMM20 expression. Additionally, while NFκB activation appeared reduced in epithelial cells, F4/80+ immune cells were elevated at baseline and post-injury, pointing to a possible dysregulation in epithelial-immune crosstalk. Conclusion: These findings identify an unexpected critical role of PKCζ in the excretion of renal tubular CaOx crystals and suggest its potential as a therapeutic target for preventing chronic kidney disease progression following crystal-induced injury. Funding: Private Foundation Support