Contrasting effects of steroids and mizoribine on macrophage activation and glomerular lesions in rat Thy-1 mesangial proliferative glomerulonephritis

Yohei Ikezumi, Toshiaki Suzuki, Tamaki Karasawa, Hiroya Hasegawa, Hiroshi Kawachi, David J. Nikolic-Paterson, Makoto Uchiyama

研究成果: Article

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Background: Macrophages with a pro-inflammatory (M1) phenotype mediate renal injury in proliferative forms of glomerulonephritis, while alternatively activated (M2) macrophages are thought to be anti-inflammatory and promote repair. Glucocorticoids, the mainstay therapy for proliferative glomerulonephritis, can induce alternative macrophage activation in vitro, but it is unknown whether this occurs in vivo and if this is required for glucocorticoid responsiveness. In addition, clinical studies have suggested that the ability of mizoribine (MZR) to suppress steroid-resistant proliferative glomerulonephritis may operate via inhibiting pro-inflammatory macrophage activation. Methods: This study examined prednisolone (PSL) and/or MZR treatment of rat Thy-1 disease - a model in which macrophages promote mesangial proliferative glomerulonephritis. Results: PSL treatment of Thy-1 nephritis induced an M2-like macrophage phenotype, but failed to modify mesangial hypercellularity and actually exacerbated global glomerulosclerosis. In contrast, MZR treatment reduced hypercellularity and glomerulosclerosis and suppressing both M1 and M2 markers of macrphage activation, with a selective reduction in CD169+ macrophages. Combined PSL/MZR treatment suppressed glomerular lesions and prevented steroid induction of an M2-like macrophage phenotype. In vitro, MZR prevented steroid induction of an M2 macrophage phenotype. Conclusions: Glucocorticoid induced alternative macrophage activation failed to ameliorate rat mesangial proliferative glomerulonephritis, whereas MZR suppression of this disease model was attributed, in part, to inhibition of M1-like pro-inflammatory macrophage activation.

元の言語English
ページ(範囲)273-282
ページ数10
ジャーナルAmerican Journal of Nephrology
31
発行部数3
DOI
出版物ステータスPublished - 03-2010

All Science Journal Classification (ASJC) codes

  • Nephrology

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