Targeting HRG-mediated tubular epithelial cell-macrophage interplay restores the endogenous defense against calcium oxalate kidney stones

Dysfunction of renal macrophagic phagocytosis is closely associated with calcium oxalate (CaOx) kidney stone formation; however, its underlying mechanisms remain poorly understood. In this study, we identified the mechanism by which histidine-rich glycoprotein (HRG)-mediated communication between renal tubular epithelial cells (RTEC) and macrophages mediates the phagocytosis of stone crystals in clinical samples, in vivo , and in vitro stone models, using integrated proteomic and transcriptomic analyses coupled with biochemical experiments. Mechanistically, RTEC exhibited reduced HRG secretion under stone-forming conditions. Reduced HRG weakens interactions with FcgammaRI (FcγRI) receptors on macrophages, thereby inhibiting downstream phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) signaling pathways, which downregulates Ras-related protein rab-20 (RAB20) expression to diminish macrophage phagocytosis of crystals and reduces interleukin-33 (IL-33) expression to inhibit M2 polarization of macrophages. These combined effects impair macrophage crystal phagocytosis, ultimately promoting the formation of CaOx kidney stones. Additionally, we found that enhancing HRG expression significantly suppresses oxalate crystal aggregation in kidneys and renal injury induced by glyoxylate (Gly). Through pharmacological analysis, we also identified Hesperidin, a natural compound derived from traditional Chinese medicine and validated in mice, which may exert protective effects against CaOx kidney stones by targeting HRG. In summary, this study reveals an HRG-based RTEC-macrophage communication axis that regulates crystal macrophagic phagocytosis, providing new insights into the prevention and treatment of CaOx kidney stones.