OBJECTIVE: The canonical Wnt/β-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.
OBJECTIVE: The canonical Wnt/β-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.
Authors: F Yesim Demirci; Xingbin Wang; Jennifer A Kelly; David L Morris; M Michael Barmada; Eleanor Feingold; Amy H Kao; Kathy L Sivils; Sasha Bernatsky; Christian Pineau; Ann E Clarke; Rosalind Ramsey-Goldman; Timothy J Vyse; Patrick M Gaffney; Susan Manzi; M Ilyas Kamboh Journal: Arthritis Rheumatol Date: 2016-01 Impact factor: 10.995