Exposure to Sodium <i>p</i>‑PerfluorousNonenoxybenzenesulfonate Induces Renal Fibrosis in Mice by DisruptingLysine Metabolism

Environmental exposure is one driving factor of chronic kidney disease (CKD), yet the intrinsic molecular mechanisms are largely unexplored. As a persistent chemical, perfluorooctanesulfonate (PFOS) is regulated due to a great potential to induce multiple diseases, including renal fibrosis, a major pathological characteristic of CKD. It is hypothesized that sodium <i>p</i>-perfluorous nonenoxybenzenesulfonate (OBS), a typical alternative to PFOS, may also induce renal fibrosis. We observed distinct renal fibrosis in mice exposed to OBS. Metabolomics analysis showed that Nα-acetyllysine was the primary metabolite biomarker, whose level decreased greatly due to its excessive consumption by lysyloxidase (LOX). This suppressed the miR-140-5p expression, promoting upregulation of <i>fibroblast growth factor 9 (FGF9)</i>, which activated the PI3K/Akt signaling pathway through <i>fibroblast growth factor receptor 3 (FGFR3)</i>, thereby enhancing proliferation and activation of fibroblasts. Supplement of Nα-acetyllysine upregulated miR-140-5p expression, reduced expressions of <i>FGF9</i> and <i>FGFR3</i>, and eventually ameliorated OBS-induced renal fibrosis. Similarly, treatment with miR-140-5p agomir and PI3K/Akt signaling pathway inhibitor LY294002 attenuated OBS-induced renal fibrosis. Taken together, OBS caused renal fibrosis through the LOX–Nα-acetyllysine–miR-140-5p–FGF9–FGFR3–PI3K/Akt–Bad–Bcl-2–fibroblast axis. The results of this study reveal a specific molecular axis for OBS to induce renal fibrosis and call for concerns in supervising the application of OBS.