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Studies have shown that arsenic exposure can cause renal fibrosis, but the underlying mechanism is still unclear. Integrating the <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> models, this study investigated the potential molecular pathways for arsenic\u2010induced renal fibrosis. In this study, SD rats were treated with 0, 5, 25, 50, and 100\u2009mg\/L NaAsO<jats:sub>2<\/jats:sub> for 8\u2009weeks via drinking water, and HK2 cells were treated with different doses of NaAsO<jats:sub>2<\/jats:sub> for 48\u2009h. The <jats:italic>in vivo<\/jats:italic> results showed that arsenic content in the rats' kidneys increased as the dose increased. Body weight decreased and kidney coefficient increased at 100\u2009mg\/L. As a response to the elevated NaAsO<jats:sub>2<\/jats:sub> dose, inflammatory cell infiltration, renal tubular injury, glomerular atrophy, tubulointerstitial hemorrhage, and fibrosis became more obvious indicated by HE and Masson staining. The kidney transcriptome profiles further supported the protein\u2013protein interactions involved in NaAsO<jats:sub>2<\/jats:sub>\u2010induced renal fibrosis. The <jats:italic>in vivo<\/jats:italic> results, in together with the <jats:italic>in vitro<\/jats:italic> experiments, have revealed that exposure to NaAsO<jats:sub>2<\/jats:sub> disturbed mitochondrial dynamics, promoted mitophagy, activated inflammation and the TGF\u2010\u03b21\/SMAD signaling pathway, and finally resulted in fibrosis. In summary, arsenic exposure contributed to renal fibrosis via regulating the mitochondrial dynamics and the NLRP3\u2010TGF\u2010\u03b21\/SMAD signaling axis. This study presented an adverse outcome pathway for the development of renal fibrosis due to arsenic exposure through drinking water.<\/jats:p>","DOI":"10.1002\/tox.24196","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T12:41:23Z","timestamp":1711024883000},"page":"3679-3693","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Arsenic exposure induced renal fibrosis via regulation of mitochondrial dynamics and the <scp>NLRP3\u2010TGF<\/scp>\u2010\u03b21\/<scp>SMAD<\/scp> signaling pathway"],"prefix":"10.1002","volume":"39","author":[{"given":"Miaomiao","family":"Ren","sequence":"first","affiliation":[{"name":"State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory &amp; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health Xiamen University  Xiamen 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