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2016 ; 18
(1
): 139
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Nuclear factor erythroid 2-related factor 2 is a critical target for the
treatment of glucocorticoid-resistant lupus nephritis
#MMPMID27301376
Ebihara S
; Tajima H
; Ono M
Arthritis Res Ther
2016[Jun]; 18
(1
): 139
PMID27301376
show ga
BACKGROUND: 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. METHODS: 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. RESULTS:
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. CONCLUSIONS: 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.
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