Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice.
Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice.
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DOI：
10.1002/emmm.201100149
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发表时间：
2011-07
影响因子：
11.1
通讯作者：
Gasser, David L.
中科院分区：
文献类型：
--
作者：
Falk, Marni J.;Polyak, Erzsebet;Zhang, Zhe;Peng, Min;King, Rhonda;Maltzman, Jonathan S.;Okwuego, Ezinne;Horyn, Oksana;Nakamaru-Ogiso, Eiko;Ostrovsky, Julian;Xie, Letian X.;Chen, Jia Yan;Marbois, Beth;Nissim, Itzhak;Clarke, Catherine F.;Gasser, David L.
线粒体呼吸链疾病的治疗由于对导致广泛变化的临床结果的细胞机制的有限理解而变得复杂。在这里，我们表明，局灶节段性肾小球病样肾病Pdss 2突变动物与原发性辅酶Q（辅酶Q）缺乏症是显着改善口服治疗普罗布考（1% w/w）。在错义突变小鼠中，无论是从断奶时还是在典型肾炎发作前3周喂食普罗布考，其抑制作用都是相似的。此外，用普罗布考治疗有症状的动物2周显著减少蛋白尿。普罗布考具有比高剂量辅酶Q10补充剂更明显的健康益处，并且独特地恢复突变肾脏中的辅酶Q9含量。普罗布考显著减轻许多中间代谢结构域的转录改变，包括过氧化物酶体增殖物激活受体（PPAR）通路信号传导。普罗布考对Pdss 2疾病的肾脏和代谢表现的有益作用尽管适度诱导氧化应激，但仍发生，并且似乎独立于其降血脂作用。相反，CoQ 9含量降低和PPAR途径信号传导改变似乎分别协调了原发性CoQ缺乏症的肾小球和全球代谢后果，这两者都可以通过口服普罗布考治疗来预防和治疗。
Therapy of mitochondrial respiratory chain diseases is complicated by limited understanding of cellular mechanisms that cause the widely variable clinical findings. Here, we show that focal segmental glomerulopathy-like kidney disease in Pdss2 mutant animals with primary coenzyme Q (CoQ) deficiency is significantly ameliorated by oral treatment with probucol (1% w/w). Preventative effects in missense mutant mice are similar whether fed probucol from weaning or for 3 weeks prior to typical nephritis onset. Furthermore, treating symptomatic animals for 2 weeks with probucol significantly reduces albuminuria. Probucol has a more pronounced health benefit than high-dose CoQ10 supplementation and uniquely restores CoQ9 content in mutant kidney. Probucol substantially mitigates transcriptional alterations across many intermediary metabolic domains, including peroxisome proliferator-activated receptor (PPAR) pathway signaling. Probucol's beneficial effects on the renal and metabolic manifestations of Pdss2 disease occur despite modest induction of oxidant stress and appear independent of its hypolipidemic effects. Rather, decreased CoQ9 content and altered PPAR pathway signaling appear, respectively, to orchestrate the glomerular and global metabolic consequences of primary CoQ deficiency, which are both preventable and treatable with oral probucol therapy.
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