Abstract
ObjectiveThe canonical WNT pathway has been implicated as playing important roles in the pathogenesis of a variety of kidney diseases. Recently, WNT pathway activity was reported to be elevated in the renal tissue of a lupus mouse model. This study aimed to evaluate the potential role of the WNT pathway in the pathogenesis of human lupus nephritis.MethodsThe expression of β-catenin was evaluated in renal biopsy specimens from lupus nephritis patients and control kidney tissues by immunohistochemistry and western blotting. Real-time polymerase chain reaction (RT-PCR) was used to detect RNA expression of β-catenin, Dkk-1 and Axin2. Plasma concentrations of Dkk-1 were measured by ELISA.ResultsImmunohistochemistry and western blotting revealed increased expression of β-catenin in the kidneys of patients with lupus nephritis compared with control kidney tissues (p<0.05), accompanied by an increase in mRNA expression of β-catenin (p<0.01) and axin2 (p<0.05).β-catenin was significantly greater in LN patients without renal interstitial fibrosis compared with those with renal interstitial fibrosis (p<0.01) at the mRNA expression level; the increase in β-catenin mRNA positively correlated with the creatinine clearance rate (Ccr) and negatively correlated with chronicity indices of renal tissue injury. Greater plasma Dkk-1 concentrations were found in LN patients compared with controls (p<0.05). Plasma Dkk-1 concentrations also correlated negatively with anti-dsDNA antibody levels and positively with serum C3 levels.ConclusionsThe canonical WNT/β-catenin signaling pathway was activated in lupus nephritis patients, accompanied by an increase in plasma levels of Dkk-1. Altered WNT/β-catenin signaling was related to the pathogenesis of lupus nephritis and might play a role in renal fibrosis.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of various autoantibodies and multiorgan involvement
The WNT pathway is activated by the binding of the WNT ligand to a seven-pass transmembrane Frizzled receptor and its coreceptor, which prevents the degradation of b-catenin, mediated by glycogen synthase kinase 3b (GSK3b). b-catenin accumulates in the cytosol and translocates to the nucleus, where it associates with lymphoid enhancer factor and T-cell factor (LEF-1/TCF) to form a transcription complex, leading to the activation of the genes involved in cell proliferation and differentiation [3].b-catenin, the central component in the canonical WNT pathway, serves as a molecular switch for the WNT pathway
MRNA expression of b-catenin was significantly greater in LN patients without renal interstitial fibrosis compared with those with renal interstitial fibrosis (-DDCt = 3.62260.240 vs. 2.93460.124, respectively, p = 0.006). (Figure 3C)
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of various autoantibodies and multiorgan involvement. The WNT pathway is activated by the binding of the WNT ligand to a seven-pass transmembrane Frizzled receptor and its coreceptor, which prevents the degradation of b-catenin, mediated by glycogen synthase kinase 3b (GSK3b). B-catenin accumulates in the cytosol and translocates to the nucleus, where it associates with lymphoid enhancer factor and T-cell factor (LEF-1/TCF) to form a transcription complex, leading to the activation of the genes involved in cell proliferation and differentiation [3].b-catenin, the central component in the canonical WNT pathway, serves as a molecular switch for the WNT pathway. The WNT signaling pathway is tightly regulated by several antagonists, including the secreted Frizzled-related proteins, WNT inhibitory factor, Cerberus and the Dickkopf protein family. Dickkopf-1(Dkk-1) is a downstream of gene of WNT signaling pathway and will be activated by WNT signaling pathway which was reported as a specific inhibitor of WNT/bcatenin signaling [4]
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