Alterations in Wnt pathway activity in mouse serum and kidneys during lupus development

Abstract

Objective. The canonical Wnt/␤-catenin pathway was recently identified as a factor in the pathogenesis of several renal diseases. The aim of this study was to evaluate Wnt signaling activity during disease development in a murine model of lupus nephritis.Methods. Wnt activity and Dkk-1 expression were serially assayed in the serum and kidneys of (NZB ؋ NZW)F 1 mice during progression of lupus nephritis. The effects of serum obtained from mice with lupus and serum-equivalent concentrations of Dkk-1 on mesangial cells were assessed in vitro.Results. Gene expression analyses revealed increased canonical Wnt pathway activity in kidneys during development of lupus nephritis, paralleled by an increase in renal and serum levels of the Wnt inhibitor Dkk-1. Sera obtained from proteinuric-stage (NZB ؋ NZW)F 1 mice showed strong Wnt-inhibitory effects in vitro. Dkk-1 concentrations comparable to those observed in lupus-prone mice induced apoptosis in tubular and mesangial cells in vitro, whereas no such effect was seen for the range of concentrations observed in young prediseased mice and control BALB/c mice.Conclusion. These data demonstrate that renal Wnt signaling activity is increased in lupus and is accompanied by an increase in renal and serum levels of Dkk-1. The Wnt pathway is involved in the turnover of extracellular matrix constituents and represents a potential mediator of the morphologic changes that occur within the glomerulus during the development of nephritis. Furthermore, increased levels of Dkk-1 serve as a potential proapoptotic stimulus in vitro and possibly in vivo and could be an important element in the initiation and progression of systemic and end-organ disease manifestations in systemic lupus erythematosus.

Leukocyte Beta-Catenin Expression Is Disturbed in Systemic Lupus Erythematosus

“…Tveita and Rekvig previously showed that β-catenin-related transcription is elevated in the kidneys of lupus-prone BWF1 mice [24]. We have also observed that renal beta catenin expression and its transcriptional targets is elevated in another mouse model of lupus, B6.Sle1.Sle3 (S3 Fig).…”

“…We and others have screened lupus-prone mice and SLE patient serum and find increased β-catenin-related markers [24]. Given the interesting role of this pathway in immunity and tolerance, and the observed changes in several circulating proteins related to this signaling pathway, we examined the potential role of this pathway in lupus.…”

Yi Qi Qing Re Gao-containing serum inhibits lipopolysaccharide-induced rat mesangial cell proliferation by suppressing the Wnt pathway and TGF-β1 expression

“…DKK-1 expression was also increased in these same conditions, and mediated c-Jun, TGF-β1, and fibronectin expression, whereas stable β-catenin expression alleviated DKK-1-induced profibrotic factors, indicating that β-catenin may be a potential therapeutic target of MC dysfunction of diabetic nephropathy (26). In immune-mediated MC injury, the Wnt pathway has been demonstrated to be involved in the anti-Thy-1.1 rat model of glomerulonephritis (27), and development of lupus nephritis (28). However, there is currently scarce in vitro evidence regarding Wnts and β-catenin expression in LPS-stimulated MCs.…”

Modulation of Inflammatory Responses by Wnt/β-Catenin Signaling in Dendritic Cells: A Novel Immunotherapy Target for Autoimmunity and Cancer

“…For example, using murine models for lupus, it has been shown that Dickkopf-1 (DKK1), a negative regulator of the Wnt/β-catenin pathway, is highly upregulated in the serum during lupus progression (55). Similarly, serum samples from lupus patients showed increased levels of DKK1, suggesting altered canonical Wnt signaling in the development of lupus (56).…”