MiR-124-3p-regulated HMGB1 is involved in arsenic-induced renal fibrosis through promoting secretion of inflammatory factors in renal tubular epithelial cells.

Arsenic is known to induce renal fibrosis, yet the specific underlying mechanism remains unclear. This study investigated whether miR-124-3p is involved in arsenic-induced renal fibrosis by regulating the HMGB1 (High-mobility group box 1)/TLR4 (Toll-like receptor 4)/NF-κB (Nuclear factor-kappa B) signaling pathway, using a combined approach of population surveys in arsenic-endemic areas, the establishment of arsenic-exposed animal models, and in vitro cellular experiments. Results showed that serum levels of IL-6 (Interleukin-6), IL-1β (Interleukin-1β) and urinary KIM-1 (Kidney injury molecule-1) were significantly elevated in the human case group (P < 0.05). With increasing concentrations of sodium arsenite (NaAsO2), mice exhibited markedly elevated urinary creatinine, urea nitrogen, and protein levels, accompanied by aggravated infiltration of inflammatory cells (macrophages and lymphocytes) in the renal interstitium. Meanwhile, collagen fiber deposition around renal tubules progressively worsened, and the expression of α-SMA (alpha-smooth muscle actin) and Collagen Ⅰ (type Ⅰ collagen) was upregulated. Following NaAsO2 treatment, miR-124-3p expression was reduced, while the mRNA and protein expression levels of HMGB1, TLR4, and NF-κB p65 were increased. A luciferase reporter assay confirmed the specific binding between miR-124-3p and HMGB1. Furthermore, overexpression of miR-124-3p significantly inhibited the HMGB1/TLR4/NF-κB signaling pathway and suppressed the expression of fibrotic factors. Collectively, our findings demonstrate that chronic arsenic exposure promotes renal fibrosis and renal injury by downregulating miR-124-3p expression, which in turn activates the HMGB1/TLR4/NF-κB signaling pathway.