Omega 3 Fatty Acids Attenuated AKI to CKD Transition and Renal Fibrosis: Identification of Anti-Fibrotic Metabolites

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Background: Renal fibrosis, recognized as a histological hallmark of CKD, has become an object of interest as a prospective therapeutic target. Recent meta-analyses showed that the patients with AKI are at high risk of developing CKD, and the concept of AKI to CKD was established. ω3 fatty acids (&omegr;3PUFA) were reported to exhibit renal protective effects. However, their renal protective mechanism has remained unclear. In this study, we aimed to investigate the effect of ω3PUFA on AKI to CKD and to identify the active fatty acid metabolites against renal fibrosis. Methods: Mice were fed a normal diet or an ω3PUFA diet. After 4 weeks of feeding, bilateral renal ischemia-reperfusion (IR) was performed. The activity of fatty acid metabolites was assessed by using human monocyte-derived cell lines (THP-1 cells) and human tubular epithelial cell lines (HK-2 cells) and rat renal fibroblasts cell lines (NRK49F cells). Results: The normal or ω3PUFA diet was fed for 4 weeks, and IR (35 min) was performed to induce severe AKI. ω3PUFA diet improved the survival after AKI as compared to the normal diet. Next, AKI to CKD model (IR: 30 min) was subjected to evaluate the effect of ω3PUFA. ω3PUFA group exhibited the suppression of tubular damage and fibrosis at day 14 after renal IR. Renal fatty acid metabolites were measured, and multivariate analysis showed a significant increase in eicosapentaenoic acid (EPA) and its metabolites (18-HEPE, 17,18-EpETE, 17,18-diHETE) in the ω3PUFA group. When THP-1 cells were stimulated with LPS and the supernatant was added to HK-2 cells, an increase in IL-6 expression was observed, whereas when THP-1 cells were co-treated with EPA's metabolites, IL-6 expression was suppressed. In NRK-49F cells, TGF-β1-stimulated upregulation of α-SMA expression was suppressed by the presence of EPA and its metabolites. Conclusions: Feeding ω3PUFA improved the survival after severe AKI and reduced tubular damage and renal fibrosis in AKI to CKD. The anti-inflammatory and anti-fibrotic effects of EPA and its metabolites were shown.

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