Exposure to Sodium p-Perfluorous Nonenoxybenzenesulfonate Induces Renal Fibrosis in Mice by Disrupting Lysine 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 p-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 fibroblast growth factor 9 (FGF9), which activated the PI3K/Akt signaling pathway through fibroblast growth factor receptor 3 (FGFR3), thereby enhancing proliferation and activation of fibroblasts. Supplement of Nα-acetyllysine upregulated miR-140-5p expression, reduced expressions of FGF9 and FGFR3, 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.