Resolvin D1 (RvD1) is a lipid-derived mediator generated during the resolution inflammation. While the immunoresolvent effects of Resolvins have been extensively studied in leukocytes, actions of Resolvins on intrinsic kidney cells have received little attention. The podocyte plays a central role in glomerular function, and podocyte damage can lead to proteinuria and glomerulosclerosis. This study examined whether RvD1 has renoprotective effects upon podocytes. We investigated a mouse model of adriamycin (ADR) nephropathy featuring rapid induction of podocyte damage and proteinuria followed by glomerulosclerosis. We identified a progressive loss of synaptopodin expression over a 28 day time-course of ADR nephropathy which was associated with increased acetylation of 14-3-3beta and reduced synaptopodin phosphorylation. Groups of mice were given once daily RvD1 treatment (4 ng/g body weight/day) starting either 30 min (early treatment) or 14 days (late treatment) after ADR injection and continued until mice were killed on day 28. Early, but not late, RvD1 treatment attenuated ADR-induced proteinuria, glomerulosclerosis and tubulointerstitial fibrosis, modified macrophages from an M1 to M2 phenotype. Early RvD1 treatment prevented the down-regulation of synaptopodin expression and changes in 14-3-3beta acetylation and synaptopodin phosphorylation. In a podocyte cell line, RvD1 was shown to prevent rapid TNF-alpha-induced down-regulation of synaptopodin expression. In transfection studies, TNF-alpha-induced a decrease in synaptopodin phosphorylation and an increase in acetylation of 14-3-3beta, resulting in disassociation between 14-3-3beta and synaptopodin. RvD1 prevented TNF-alpha induced post-translational modification of synaptopodin and 14-3-3beta proteins, and maintained the synaptopodin/14-3-3beta interaction. Furthermore, replacement of lysine K51, or K117+K122 in 14-3-3beta with glutamine, to mimic lysine acetylation, significantly reduced the interaction between 14-3-3beta and synaptopodin. In conclusion, our studies provide the first evidence that RvD1 can protect against podocyte damage by preventing down-regulation of synaptopodin through inhibition of 14-3-3beta/synaptopodin dissociation. RvD1 treatment may have potential application in the treatment of chronic kidney disease.