Fig. 8. Schematic diagram of proposed mechanism of crystal-induced Ca²⁺ signaling regulating downstream effects.

Crystal internalization via endocytosis elicits prolonged Ca²⁺ entry, ER stress responses, ROS production, oxidative stress, plasma membrane (PM) damage, and cell death in HK2 cells. ER stress responses include ER morphological changes and upregulation of ER stress genes. Crystal internalization promotes upregulation of SOCE components: STIM1/2 and ORAI3 which induces prolonged Ca²⁺ entry and leads to a continuous rise in [Ca²⁺]_i, causing ROS generation, oxidative stress, and apoptosis/necrosis. CaOx Calcium Oxalate, CaP Calcium Phosphate, CaSR Calcium Sensing Receptor, CLDN Claudin; ER Endoplasmic Reticulum, ERN Endoplasmic Reticulum to Nucleus Signaling, GAPDH Glyceraldehyde 3-phosphate dehydrogenase, GPCR G-protein-coupled Receptor, GRP78 glucose-regulated protein, Mixed CaP + CaOx, PM Plasma Membrane, ROCE Receptor Operated Ca²⁺ Entry, ROS Reactive Oxygen Species, SOCE Store Operated Ca²⁺ Entry, STIM Stromal Interaction Molecule