Effects of calciprotein particles on EMT induction in an in vitro 3D‐cultured proximal tubule epithelial cell model of CKD

Calciprotein particles (CPPs) are blood-borne circulating nanoparticles composed of calcium phosphate and proteins that are known to exacerbate pathological processes such as chronic kidney disease-mineral bone disorder (CKD-MBD). Despite the significant interest in CKD-MBD pathogenesis, research directly addressing CPP-induced fibrosis in renal proximal tubules is rare, largely owing to the lack of suitable in vitro tissue models. Our study confirmed that 3D-cultured renal proximal tubule epithelial cells (PTECs) exhibited enhanced pathological characteristics compared to 2D-cultured PTECs when treated with CPPs, a key factor in CKD-MBD, and the uremic toxin. 3D-cultured PTECs under CKD-inducing conditions by CPPs were associated with epithelial-mesenchymal transition (EMT), mediated by transforming growth factor-β1 (TGF-β1), with notable changes in early EMT marker expression. Furthermore, this was attributed to increased expression of the calcium-sensing receptor (CASR), a receptor for CPPs, and activation of the downstream cell division control protein 42 (CDC42), leading to EMT progression. This study underscores the potential of PTEC-on-a-chip systems to serve as drug testing models, given the heightened sensitivity of these cells to external environments. This approach provides a better understanding of the pathological features of CKD and could contribute to the development of more effective in vitro models and therapeutics.