Abstract
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.
Highlights
Resolvin D1 (RvD1) is a lipid mediator biosynthesized from docosahexaenoic acid during the resolution of inflammation [1]
RvD1 treatment substantially inhibited the development of proteinuria and significantly improved renal function by day 28 in ADR nephropathy (Fig. 1F&G)
RvD1 treatment significantly reduced the development of glomerulosclerosis, tubular damage, cast formation and interstitial fibrosis (Fig. 2 and Fig. 3A&B)
Summary
Resolvin D1 (RvD1) is a lipid mediator biosynthesized from docosahexaenoic acid during the resolution of inflammation [1]. Compared with RvD1, 17(R)-RvD1 resists rapid inactivation by eicosanoid oxidoreductases [2] Both RvD1 and 17(R)RvD1 modulate allergic airway response and promote macrophage clearance of allergens from the airways in an allergic mouse model [4]. Mice with mutations in synaptopodin are highly susceptible to podocyte damage and glomerular injury, as shown by the prolonged proteinuria seen when challenged with a dose of lipopolysaccharide that causes only transient proteinuria in wild type mice [10]. It was shown that cyclosporine A can prevent de-phosphorylation of synaptopodin resulting in maintenance of the synaptopodin/14-3-3b interaction and normal synaptopodin function, thereby protecting mice from lipopolysaccharide-induced transient proteinuria [8]
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