Chronic Exposure to NaAsO ₂ Induces Renal Fibrosis by Modulating Gut Microbiota-Mediated AhR/NLRP3 Inflammasome Signaling Pathway

Arsenic is an environmental contaminant with potent renal toxicity. Accumulating evidence has indicated that gut microbiota dysbiosis plays an important role in kidney disease. However, the role of gut microbiota in arsenic-exposure-induced renal injury remains unclear. In our study, chronic exposure to NaAsO 2 and fecal microbiota transplantation (FMT) from NaAsO 2 -exposed mice increased intestinal permeability and elevated renal indoxyl sulfate (IS), a key metabolite of gut microbiota, which promoted renal fibrosis and activated the AhR/NLRP3 inflammasome signaling pathway. Moreover, AST-120, a non-specific adsorbent, alleviated chronic NaAsO 2 exposure-induced renal fibrosis by reducing the IS level in mice. In HK-2 cells, IS mediated NaAsO 2 -induced fibrosis via the AhR/NLRP3 inflammasome signaling pathway. Collectively, we confirmed that chronic exposure to NaAsO 2 caused renal fibrosis and intestinal barrier dysfunction. Meanwhile, the gut–kidney axis plays a significant role in the mechanism of NaAsO 2 -induced renal fibrosis, providing a new therapeutic target for the prevention and treatment of arseniasis.