ER stress induced extracellular vesicles secretion from macrophages promotes calcium oxalate crystals formation in kidney.

Macrophages are involved in the development of kidney stone disease, and substantial research suggests that macrophage-derived extracellulr vesicles (Mφ-EVs) may play a pivotal role in this process. However, the impact of Mφ-EVs on kidney stone formation and the mechanisms of EVs secretion remain unclear. Here we found that calcium oxalate (CaOx) crystals stimulation leads to increased inflammation and enhanced secretion of extracellular vesicles (EVs) in macrophages. Interestingly, these EVs can be absorbed by renal cells, significantly promoting renal tubular damage and facilitating the formation of CaOx crystals in mouse kidneys. Mechanistically, CaOx crystal stimulation activates endoplasmic reticulum stress (ERS)-related proteins, particularly PKR-like ER kinase (PERK), resulting in the production of EVs containing glucose-regulated protein 94 (GRP94). Concurrently, this process induces lysosomal dysfunction, inhibiting the degradation of EVs by lysosomes and ultimately leading to their release. Knocking down PERK in macrophages could reduce the Mφ-EVs secretion significantly, which decreased in the accumulation of CaOx crystals in the mouse kidneys. Together, our research uncovers a novel mechanism by which CaOx crystal-induced ERS and lysosomal dysfunction in macrophages promote the secretion of EVs, thereby facilitating kidney stone formation. This finding presents a promising therapeutic target for future interventions.