IL-6 exacerbates calcium oxalate kidney stones by promoting inflammatory responses and crystal adhesion via p38 MAPK signaling activation.

Kidney stones (KS) represent a complex and globally prevalent disease; however, the mechanisms underlying their formation are not fully understood. Inflammatory responses and crystal aggregation are recognized as critical factors in KS pathogenesis. Interleukin-6 (IL-6) is widely recognized as an inflammatory mediator; however, its precise contribution to calcium oxalate (CaOx) KS formation has not been fully elucidated. This study aimed to explore the detailed mechanism through which IL-6 influences CaOx KS formation. To achieve this, a rat model for CaOx nephrolithiasis was developed by administrating drinking water containing 1% ethylene glycol (EG). Concurrently, an in vitro model of cellular injury was established by treating human renal proximal tubular epithelial cells (HK-2) with calcium oxalate monohydrate (COM) crystals. Employing various molecular biology and immunological techniques, the specific role of IL-6 in the formation of CaOx stones was comprehensively examined. The data indicated significantly elevated IL-6 expression in both in vivo and in vitro models of CaOx KS. Increased IL-6 exacerbated inflammatory responses during stone formation, triggered activation of the p38 MAPK signaling pathway, and promoted higher expression levels of osteopontin (OPN) and CD44. These molecular alterations enhanced adhesion between renal tubular epithelial cells (RTECs) and crystals, consequently facilitating crystal aggregation, nucleation, and accelerating overall stone formation. In summary, the study illustrates that IL-6 accelerates CaOx KS development through activation of the p38 MAPK signaling pathway, amplifying inflammation, and promoting crystal-cell adhesion. Thus, IL-6 emerges as a promising therapeutic target for interventions in CaOx nephrolithiasis.