HMGB1 Regulates the Formation of Calcium Oxalate-Induced Kidney Stones via Modulating the PI3K/AKT Signaling Pathway

Background: High mobility group box 1 (HMGB1) participates in regulating autophagy and cell apoptosis in the cytoplasm and plays a role in various kidney diseases. However, no study has focused on the role of the HMGB1/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB, also called AKT) signaling pathway in kidney stone formation. The aim of this study was to elucidate the role of HMGB1 via the PI3K/AKT axis in calcium oxalate monohydrate (COM)-induced kidney stone formation, which might lead to novel research targets for the treatment of kidney stones. Methods: The human kidney-2 (HK-2) cell line was cultured and treated with si-HMGB1, si-negative control (NC), or PI3K agonist 740 Y-P (1 mu M). In vitro kidney stone models were established using COM and calcium oxalate (CaOx) crystals. HMGB1, AKT and PI3K levels in each group of cells were measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. Flow cytometry was utilized to measure the rate of cellular apoptosis. Results: CaOx crystal adhesion was enhanced on the surface of the HK-2 cells stimulated by COM and CaOx, and HMGB1 expression was upregulated. The proportion of apoptotic cells was elevated in HK-2 cells after stimulation with CaOx and COM. Knockdown of HMGB1 inhibited CaOx crystal-cell adhesion and reduced the apoptosis rate in COM-treated HK-2 cells. Activation of the PI3K/AKT pathway counteracted the impact of HMGB1 knockdown on the adhesion of CaOx crystals to cells. Conclusions: Inhibiting the HMGB1/PI3K/AKT axis could reduce the proportion of apoptosis and improve crystal-cell adherence.