Atypical Protein Kinase C Zeta is Required for Renal Calcium-Oxalate Crystal Clearance

Kidney stones, affecting 1 in 10 people, form due to the buildup of renal crystals. Previously, we recognized that calcium oxalate (CaOx) crystal deposition triggers reversible tubule dilation to expel renal crystals. Protein Kinase C Zeta (aPKC𝜁) is a protein we previously recognized as an important mediator during kidney disease progression. This study investigates whether aPKC𝜁 also plays a role in managing CaOx crystal deposition. To explore this, we administered a sodium oxalate (NaOx) diet to wild-type and aPKC𝜁-knockout (KO) mice for up to 14 days, followed by a 28 day washout after cessation of NaOx treatment. In uninjured wild-type mice, we observed low aPKC𝜁 expression primarily on the apical side of renal tubular epithelial cells. In response to injury, wild-type mice showed significant upregulation and diffusion of aPKC𝜁 throughout the kidney, peaking at 7 days post-injury. Both groups displayed tubule dilation and crystal accumulation, but aPKC𝜁-KO mice exhibited more severe injury, including greater tubule dilation, crystal accumulation, inflammation, and fibrosis, leading to mortality around 10 days post-injury. We are now exploring how aPKC𝜁 may regulate crystal clearance and, due to its apical localization, hypothesize that it may regulate tubular epithelial cell cilia, which extend from the apical side into the tubule lumen and may be critical mediators of tubule dilation and crystal expulsion. Altogether, these findings highlight the critical role of aPKC𝜁 in managing CaOx crystal deposition and suggest its potential as a therapeutic target for preventing chronic kidney disease progression following crystal-induced injury.

Faculty Mentor: Thomas Weimbs

Project Mentors: Melina Messing, Nickolas Holznecht, Jacob A. Torres