Dataset Information

Precision Targeting of NF-κB Signaling in Lupus Nephritis.

ABSTRACT: Lupus Nephritis (LN) is the leading cause of morbidity and mortality from Systemic Lupus Erythematosus (SLE) and enhanced activation of the transcription regulator nuclear factor kappa B (NF-κB) is implicated as a central player in the development and progression of LN. SLE and LN are proposed to develop through a "two-hit" process of genetic mutation or variants providing susceptibility to disease provoking molecular events in response to environmental triggers (viral infection, medication, etc.). Many of the susceptibility genes identified in association with LN are involved in NF-κB regulation and loss of function of some of the protein products in animal's results in protection from or development of SLE and LN phenotypes. This short commentary will discuss these factors and implications in precision treatment of LN.

SUBMITTER: Caster DJ

PROVIDER: S-EPMC9245607 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Precision Targeting of NF-κB Signaling in Lupus Nephritis.

Caster Dawn J DJ Powell David W DW

Lupus (Los Angeles) 20201228 1

Lupus Nephritis (LN) is the leading cause of morbidity and mortality from Systemic Lupus Erythematosus (SLE) and enhanced activation of the transcription regulator nuclear factor kappa B (NF-κB) is implicated as a central player in the development and progression of LN. SLE and LN are proposed to develop through a "two-hit" process of genetic mutation or variants providing susceptibility to disease provoking molecular events in response to environmental triggers (viral infection, medication, etc ...[more]

PMID: 35784620

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Project description:BackgroundLupus 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.MethodsBeginning 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.ResultsWe 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).Conclusion1,25-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.

Dataset Information

Precision Targeting of NF-κB Signaling in Lupus Nephritis.

Publications

Precision Targeting of NF-κB Signaling in Lupus Nephritis.

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