Resolvin D1 protects podocytes in adriamycin-induced nephropathy through modulation of 14-3-3β acetylation.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

14-3-3 Proteins/*genetics ; Acetylation/*drug effects ; Docosahexaenoic Acids/*pharmacology ; Doxorubicin/*pharmacology ; Kidney Diseases/*drug therapy ; Kidney Glomerulus/*drug effects ; Podocytes/*drug effects; 14-3-3 Proteins/metabolism ; Animals ; Cell Line ; Disease Models, Animal ; Down-Regulation/drug effects ; Down-Regulation/genetics ; HEK293 Cells ; Humans ; Kidney Diseases/chemically induced ; Kidney Diseases/genetics ; Kidney Diseases/metabolism ; Kidney Glomerulus/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Phosphorylation/genetics ; Podocytes/metabolism ; Protein Processing, Post-Translational/drug effects ; Protein Processing, Post-Translational/genetics ; Tumor Necrosis Factor-alpha/metabolism

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 14-3-3β 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 14-3-3β acetylation and synaptopodin phosphorylation. In a podocyte cell line, RvD1 was shown to prevent rapid TNF-α-induced down-regulation of synaptopodin expression. In transfection studies, TNF-α-induced a decrease in synaptopodin phosphorylation and an increase in acetylation of 14-3-3β, resulting in disassociation between 14-3-3β and synaptopodin. RvD1 prevented TNF-α induced post-translational modification of synaptopodin and 14-3-3β proteins, and maintained the synaptopodin/14-3-3β interaction. Furthermore, replacement of lysine K51, or K117+K122 in 14-3-3β with glutamine, to mimic lysine acetylation, significantly reduced the interaction between 14-3-3β 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 14-3-3β/synaptopodin dissociation. RvD1 treatment may have potential application in the treatment of chronic kidney disease.

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0 (14-3-3 Proteins)
0 (Microfilament Proteins)
0 (Synpo protein, mouse)
0 (Tumor Necrosis Factor-alpha)
0 (resolvin D1)
25167-62-8 (Docosahexaenoic Acids)
80168379AG (Doxorubicin)

Date Created: 20130711 Date Completed: 20140424 Latest Revision: 20211021

20240829

PMC3696081

10.1371/journal.pone.0067471

23840712