THU0051 Sodium Chloride Drives Lupus Nephritis via the Induction of Pathogenic SGK1 Pathways. (10th June 2014)

• Record Type: Journal Article
• Authors: Yang, X.; Feng, X.; Lu, L.; Sun, L.
• Is Part Of: Annals of the rheumatic diseases. Volume 73:Supplement 2(2014)
• Page Start: 193
• Page End: 194
• Publication Date: 2014-06-10
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2014-eular.2413
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Evidences have suggested excess NaCl content in diet is a potential environmental risk factor for autoimmune diseases. Na+ transport and NaCl homeostasis are controlled by the serum and glucocorticoid- inducible serine/threonine protein kinase 1 (SGK1), which is related to transforming growth factor-β (TGF-β) and has been shown to elevate in kidneys from glomerulonephritis patients. However, it remains unclear whether high salt diet (HSD) could induce lupus nephritis (LN) via the activation of SGK1 pathways. Objectives: We aimed to identify the effect of HSD on the severity of LN and to assess whether SGK1 pathway was involved in this process. Methods: Female lupus-prone MRL/lpr mice and C57/BL6 mice were divided into four groups (n=5 in each group) and fed with normal diet and tap water ad libitum (control) or sodium-rich chow containing 4% NaCl and tap water containing 1% NaCl ad libitum (HSD) daily from 10 weeks age to 30 weeks age. Levels of serum antinuclear (ANA) antibody, anti-double-stranded DNA (anti-dsDNA) antibody, TGF-β, Interleukin (IL)-17, IL-6, IL-10 were measured by ELISA, and the expressions of SGK1 were quantified by real-time PCR. 24 hour urine protein was detected using Coomassi brilliant blue method. The expression of IgG, C3, TGF-β and SGK1 in kidney was detected by immunohistochemistry staining. The percentages of Th17 cells, Treg cells, B10 cells (IL-10-producing CD1d hi CD5 + ) and plasma cells in total peripheral blood mononuclear cells (PBMCs) and splenic cells were determined by flow cytometry. To confirm the effect of HSD in animal study, PBMCs from 20 female patients with lupus nephritis and 11 healthy donors were collected and co-cultured with NaCl (0/20/40/80 mM) with or without the presence of SGK1 inhibitor for 7 days. Results: The most significant increases of ANA/dsDNA titer, TGF-β, IL-17, IL-6, IL-10, SGK1 levels and the amount of the 24h urine protein were detected in the HSD treated MRL/lpr mice group compared with the other 3 groups, in which the expression levels of TGF-β and SGK1 were coordinately upregulated in both serum and kidney. Percentages of Th17 cells and plasma cells were elevated, while Treg cells and B10 cells were reduced in the HSD treated MRL/lpr groups compared with the other groups. Similarly, increased levels of TGF-β, IL-17, IL-6, IL-10 and SGK1 were also detected in LN patients in comparison with healthy subjects. In vitro human studies demonstrated that NaCl could increase the numbers of Th17 cells and plasma cells, and decrease the numbers of Treg cells and B10 cells dose-dependently. After the intervention with SGK1 inhibitor, the percentages of Th17 cells and plasma cells and the expression levels of IL-17, IL-6, IL-10, TGF-β and SGK1 are all declined. Conclusions: Our study demonstrates excessive intake of salt in diet is a causative factor for LN, which is related to the activation of SGK1 pathway. Disclosure of Interest: : None declared DOI: 10.1136/annrheumdis-2014-eular.2413