Mizoribine halts kidney fibrosis in childhood IgA nephropathy: association with modulation of M2-type macrophages
Mizoribine halts kidney fibrosis in childhood IgA nephropathy: association with modulation of M2-type macrophages
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DOI：
10.1007/s00467-022-05786-w
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发表时间：
2022-11
影响因子：
3
通讯作者：
Y. Ikezumi;Masatoshi Yoshikane;Tomomi Kondoh;Y. Matsumoto;N. Kumagai;M. Kaneko;H. Hasegawa;Takeshi Yamada;Toshiaki Suzuki;D. Nikolic-Paterson
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作者：
Y. Ikezumi;Masatoshi Yoshikane;Tomomi Kondoh;Y. Matsumoto;N. Kumagai;M. Kaneko;H. Hasegawa;Takeshi Yamada;Toshiaki Suzuki;D. Nikolic-Paterson
背景免疫抑制剂咪唑立宾(MIZ)可延缓儿童IgA肾病(IgAN)的进展。本研究旨在探讨MIZ对CD163+M2型巨噬细胞的影响是否与儿童IgAN肾脏纤维化有关。方法将90例儿童Ig AN患者分为单用强的松龙组(P组，n= 42)和PSL加MIZ组(PM组，n= 48)，疗程2年。用地塞米松(Dex)或地塞米松(Dex+Miz)刺激正常人单核细胞来源的巨噬细胞，并用DNA微阵列进行分析。结果进入P组和PM组的患者首次活检的临床和组织学结果相同。两种治疗方法都改善了蛋白尿和血尿，并在两年的疗程中维持了正常的肾功能。在2年的活检中，P组表现为系膜基质扩张增加，肾小球节段性或球状硬化增加，间质纤维化增加；然而，PM组没有肾脏纤维化的进展。这些保护作用与PM组肾小球和间质CD163+巨噬细胞的数量减少有关。在培养的人巨噬细胞中，地塞米松诱导细胞因子和生长因子的上调，而MIZ可以阻止这一上调。MIZ还抑制地塞米松诱导的CD300E的表达，CD300E是一种可防止单核细胞凋亡的激活受体。P组CD163+巨噬细胞表达CD300e明显，经MIZ治疗后CD300e表达减少。结论MIZ可延缓PSL治疗儿童IgAN肾纤维化的进展。这与CD163+和CD163+CD300e+巨噬细胞数量的减少有关，加上体外研究结果表明MIZ可以抑制类固醇诱导的促纤维化分子的巨噬细胞表达。
BackgroundThe immunosuppressant mizoribine (Miz) can reduce progression of childhood IgA nephropathy (IgAN). This study examined whether Miz affects CD163+M2-type macrophages which are associated with kidney fibrosis in childhood IgAN.MethodsA retrospective cohort of 90 children with IgAN were divided into groups treated with prednisolone (PSL) alone (P group;n= 42) or PSL plus Miz (PM group;n= 48) for a 2-year period. Normal human monocyte-derived macrophages were stimulated with dexamethasone (Dex), or Dex plus Miz, and analyzed by DNA microarray.ResultsClinical and histological findings at first biopsy were equivalent between patients entering the P and PM groups. Both treatments improved proteinuria and haematuria, and maintained normal kidney function over the 2-year course. The P group exhibited increased mesangial matrix expansion, increased glomerular segmental or global sclerosis, and increased interstitial fibrosis at 2-year biopsy; however, the PM group showed no progression of kidney fibrosis. These protective effects were associated with reduced numbers of glomerular and interstitial CD163+macrophages in the PM versus P group. In cultured human macrophages, Dex induced upregulation of cytokines and growth factors, which was prevented by Miz. Miz also inhibited Dex-induced expression ofCD300E, an activating receptor which can prevent monocyte apoptosis. CD300e expression by CD163+macrophages was evident in the P group, which was reduced by Miz treatment.ConclusionMiz halted the progression of kidney fibrosis in PSL-treated pediatric IgAN. This was associated with reduced CD163+and CD163+CD300e+macrophage populations, plus in vitro findings that Miz can suppress steroid-induced macrophage expression of pro-fibrotic molecules.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information