Nuclear factor erythroid 2-related factor 2 is a critical target for the treatment of glucocorticoid-resistant lupus nephritis.
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 Nrf2 activators on human renal mesangial cells (HRMCs) and the development of lupus nephritis (LN) in mice.



To 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.



Nrf2 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.



Nrf2 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.
Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan. ebihara@med.tohoku.ac.jp.
Shin
S
Ebihara
Department of Clinical laboratory, National Hospital Organization Mito Medical Center, 280 Sakuranosato, Ibaraki, higashi-ibaraki, Ibaraki, 311-3193, Japan.
Hideaki
H
Tajima
Department of Clinical laboratory, National Hospital Organization Mito Medical Center, 280 Sakuranosato, Ibaraki, higashi-ibaraki, Ibaraki, 311-3193, Japan.
Masao
M
Ono
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000069462:Dimethyl Fumarate / Q000494:pharmacology; D004195:Disease Models, Animal; D004351:Drug Resistance; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology; D008181:Lupus Nephritis / Q000378:metabolism / Q000473:pathology*; D050527:Mesangial Cells / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism*; D011239:Prednisolone / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D013454:Sulfoxides
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D013454:Sulfoxides; D011239:Prednisolone; D000069462:Dimethyl Fumarate; C016766:sulforaphane
Dimethyl fumarate; Glucocorticoid resistance; Lupus nephritis; Mesangial cell; Nrf2; Pristane