1,25-dihydroxyvitamin D3 ameliorates lupus nephritis through inhibiting the NF-κB and MAPK signalling pathways in MRL/lpr mice

Abstract

Background Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus (SLE). However, the aetiology and pathogenesis of LN remain unknown. 1,25-dihydroxyvitamin D3 [1,25-(OH)2-VitD3] is the active form of vitamin D, and it has been shown to perform important functions in inflammatory and immune-related diseases. In this study, we investigated the time-dependent effects of 1,25-dihydroxyvitamin D3 and explored the underlying mechanism in MRL/lpr mice, a well-studied animal model of LN. Methods Beginning at 8 weeks of age, 24-h urine samples were collected weekly to measure the levels of protein in the urine. We treated female MRL/lpr mice with 1,25-dihydroxyvitamin D3 (4 μg/kg) or 1% DMSO by intraperitoneal injection twice weekly for 3 weeks beginning at the age of 11 weeks. The mice were separately sacrificed, and serum and kidney samples were collected at the ages of 14, 16, 18, and 20 weeks to measure creatinine (Cr) levels, blood urea nitrogen (BUN) levels, histological damage, immunological marker (A-ds DNA, C1q, C3, IgG, IgM) levels, and inflammatory factor (TNF-α, IL-17, MCP-1) levels. Furthermore, the nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinase (MAPK) signalling pathways were also assessed to elucidate the underlying mechanism. Results We found that MRL/lpr mice treated with 1,25-dihydroxyvitamin D3 displayed significantly attenuated LN. VitD3-treated mice exhibited significantly improved renal pathological damage and reduced proteinuria, BUN, SCr, A-ds DNA antibody and immune complex deposition levels (P < 0.05) compared with untreated MRL/lpr mice. Moreover, 1,25-dihydroxyvitamin D3 inhibited the complement cascade, inhibited the release of proinflammatory cytokines, such as TNF-α, IL-17, and MCP-1, and inhibited NF-κB and MAPK activation (P < 0.05). Conclusion 1,25-dihydroxyvitamin D3 exerts a protective effect against LN by inhibiting the NF-κB and MAPK signalling pathways, providing a potential treatment strategy for LN. Interestingly, the NF-κB and MAPK signalling pathways are time-dependent mediators of LN and may be associated with lupus activity.

Effects of Dietary Oleacein Treatment on Endothelial Dysfunction and Lupus Nephritis in Balb/C Pristane-Induced Mice

“…As a consequence, the p65 and p50 subunits translocate to the nucleus, regulating the expression of several inflammatory mediators [ 5 ]. We observed decreased expression of IκB in the cytosol and increased translocation of p65 and p50 subunits to the nucleus in pristane-induced mouse kidneys, in agreement with previous work [ 5 , 35 ]. However, dietary OLA decreased the translocation of p65 and p50 to the nucleus, blocking NF-κB activation.…”

“…In accordance with our previous results [ 7 , 9 , 13 ], we observed increased phosphorylation of p38, JNK, and ERK in kidneys from lupic animals. Moreover, our data are in agreement with those from MRL/lpr mice [ 35 ]. Thus, these findings may suggest a connection between the activation of MAPKs and SLE disease.…”

“…The deposits of the IgG and IgM immunocomplexes play a critical role in the pathogenesis of lupus-induced nephritis [ 35 ]. Thus, we evaluated the presence of IgG and IgM immunocomplexes by IHC and IF in renal sections ( Figure 3 ).…”

C/EBPβ isoform‐specific regulation of podocyte pyroptosis in lupus nephritis‐induced renal injury

“…A significant rise in the levels of serum CRE, BUN, and urinary protein is a common sign of loss of renal function in LN patients. The levels of urinary protein, serum CRE, and BUN all sharply increased in the mice with LN as nephritis advanced [22]. In this study, the levels of urinary protein, serum CRE, anti‐dsDNA IgG, and BUN in the two groups of mice were measured to clarify the relationship between Cebpb mRNA level and the degree of renal function.…”

New Potentiality of Bioactive Substances: Regulating the NLRP3 Inflammasome in Autoimmune Diseases

“…These findings partially explain the protective effect of vitamin D in autoimmune diseases, including its ability to reduce the levels of inflammatory cytokines and ROS in RA patients [190]. Additionally, vitamin D improves renal damage in lupus mouse models by inhibiting the NF-κB and MAPK pathways and reducing autoantibody levels [191].…”