title: Effect of E6060 [4-{5-[7-fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic acid], a novel subtype-selective retinoid, on lupus-like nephritis in female (NZBxNZW)F1 mice.
abstract: Disease amelioration by retinoids in various nephritic models has been reported from either immunological or pathophysiologic viewpoints. It has also been reported that retinoids exert immunosuppressive effects in a retinoic acid receptor (RAR)-alpha-dependent manner. In particular, synthetic retinoid agonists with selectivity to RAR-alpha have been reported to have a remarkable disease-ameliorating effect in some immune disease models via their potent immunosuppressive activities; however, there has been no report in which the effect of RAR-alpha-selective agonists in the nephritic models was examined. In this report, we investigated the effect of a newly synthesized RAR-alpha-selective retinoid agonist, E6060 [4-{5-[7-fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic acid], on the disease progression in a murine lupus nephritis model. Female (NZBxNZW)F1 mice were prophylactically treated with E6060 from 5 months of age, and their nephritic (proteinuria, blood urea nitrogen) and immunological parameters (serum anti-DNA autoantibodies and total serum immunoglobulins) were monitored with age up to 10 months old. E6060 at 0.03 and 0.1 mg/kg (once daily, p.o.) significantly improved survival rate and prevented the development of proteinuria in (NZBxNZW)F1 mice. Anti-DNA autoantibodies and total serum IgG were also significantly reduced in the E6060-treated mice. Among IgG isotypes, IgG2a was substantially reduced by E6060 treatment, indicating reduced T helper 1 responses in E6060-treated mice. In accordance with this possibility, elevation of serum interleukin-12 (p40) in old female (NZBxNZW)F1 mice was significantly inhibited by E6060 treatment. Our data suggest that the RAR-alpha-selective retinoid E6060 is a promising candidate of new remedy for lupus nephritis in systemic lupus erythematosus patients.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba Science City, Ibaraki, 300-2635, Japan. t-yamauchi@hhc.eisai.co.jp
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Akira
authors.initials: A
authors.lastname: Ishibashi
authors.forename: Kohdoh
authors.initials: K
authors.lastname: Shikata
authors.forename: Naoki
authors.initials: N
authors.lastname: Tokuhara
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Seino
authors.forename: Seiichi
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Nagai
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use*; D001806:Blood Urea Nitrogen; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D018664:Interleukin-12 / Q000097:blood; D007668:Kidney / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008814:Mice, Inbred NZB; D011507:Proteinuria / Q000188:drug therapy; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000187:drug effects; D000072482:Retinoic Acid Receptor alpha; D015996:Survival Rate
chemical_list: C498503:4-(5-(7-fluoro-4-(trifluoromethyl)benzo(b)furan-2-yl)-1H-2-pyrrolyl)benzoic acid; D000974:Antibodies, Antinuclear; D001565:Benzoates; D001572:Benzofurans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011758:Pyrroles; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D018664:Interleukin-12