Nuclear factor erythroid 2-related factor 2 is a critical target for the treatment of glucocorticoid-resistant lupus nephritis.

Shin Ebihara,Hideaki Tajima,Masao Ono

doi:10.1186/s13075-016-1039-5

Shin Ebihara, Hideaki Tajima + Show 1 more

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https://doi.org/10.1186/s13075-016-1039-5

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Abstract

BackgroundDimethyl fumarate (DMF), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, has been proven effective for the systemic treatment of multiple sclerosis. The aim of this study is to evaluate the anti-inflammatory effects of Nrf2 activators on human renal mesangial cells (HRMCs) and the development of lupus nephritis (LN) in mice.MethodsTo assess Nrf2 activation in vitro, HRMCs were treated with safe doses of Nrf2 activators and prednisolone. The expression levels of Nrf2 and its target genes were measured using quantitative reverse transcription PCR and enzyme-linked immunosorbent assay. The anti-inflammatory effects of these compounds were assessed by measuring tumor necrosis factor alpha-induced cytokine secretion. Experimental LN was induced in female BALB/c mice by a single intraperitoneal injection of pristane. The urine albumin-to-creatinine ratio was measured at 20 weeks after injection. Pathological changes as well as protein and mRNA expression levels were assessed in the kidney obtained at the experimental end point. Oral administration of DMF or prednisolone to these mice was initiated after pristane injection.ResultsNrf2 activators such as sulforaphane and DMF showed anti-inflammatory effects in HRMCs, whereas glucocorticoid (prednisolone) showed partial effects. Moreover, DMF ameliorated the development of kidney diseases in pristane-induced LN mice, whereas glucocorticoid had no effect.ConclusionsNrf2 activators showed stronger anti-inflammatory and organ-protective effects than glucocorticoid in the kidney. Thus, Nrf2 activators are potential therapeutic targets in glucocorticoid-resistant LN in humans.

Highlights

Dimethyl fumarate (DMF), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, has been proven effective for the systemic treatment of multiple sclerosis
Upregulation of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) expression in human renal mesangial cells (HRMCs) by Nrf2 activators As shown in Fig. 1a, Nrf2 activators such as sulforaphane and DMF induced the binding of Nrf2 to immortalized consensus antioxidant response element (ARE) in HRMCs
To determine whether nuclear factor (NF)-kB is involved in Nrf2 pathway, the effects of Nrf2 activators on TNF-αinduced NF-kB DNA binding were examined in terms of NF-kB activation

Summary

Introduction

Dimethyl fumarate (DMF), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, has been proven effective for the systemic treatment of multiple sclerosis. The aim of this study is to evaluate the anti-inflammatory effects of Nrf activators on human renal mesangial cells (HRMCs) and the development of lupus nephritis (LN) in mice. 25–50 % of SLE patients develop lupus nephritis (LN), which is initiated by the deposition of immune complexes within the renal parenchyma leading to complement activation, mesangial expansion, and induction of inflammatory and fibrotic processes, resulting in glomerulonephritis and progressive renal. The polymorphisms in the nuclear factor erythroid 2related factor 2 (Nrf2) genes appear to confer a risk for developing LN [4]. The activation of Nrf leads to organ-protective effects and to anti-inflammatory effects by inhibition of nuclear factor (NF)-kB activation. Antioxidant response of Nrf and NQO1, which functions in the downstream of Nrf, was demonstrated in the kidney of patients with LN; it was not determined whether the response modified the disease activity or not [8]

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