A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis.
A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis.
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DOI：
10.1042/bj20130825
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发表时间：
2013-12-15
期刊：
影响因子：
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通讯作者：
Ishii S
中科院分区：
文献类型：
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作者：
Taguchi A;Maruyama H;Nameta M;Yamamoto T;Matsuda J;Kulkarni AB;Yoshioka H;Ishii S
Fabry病是一种溶酶体储存障碍，由于α-半乳糖苷酶A(α-GalA)活性不足，中性鞘糖脂，主要是球三糖神经酰胺(Gb3)积聚。α-GalA基因敲除(GLAKO)小鼠已被用作法布里病的模型，但它没有任何症状异常。在本研究中，我们通过将GLAko小鼠与表达人Gb3合成酶的转基因小鼠杂交，建立了一个有症状的小鼠模型(G3Stg/GLAko)。G3Stg/GLAko小鼠主要脏器Gb3水平较高，5-25周龄血清Gb3水平是同龄GLAko小鼠的6-10倍。G3Stg/GLAko小鼠表现为进行性肾损害，3周龄时出现蛋白尿，5周龄时尿渗透压降低，10周时出现多尿，15周时血尿素氮升高。静脉注射重组人α-GalA可显著减少G3Stg/GLAKO小鼠的尿量和尿白蛋白浓度。这些数据表明，G3Stg/GLAko小鼠的症状表型中Gb3积聚是主要致病因素，该小鼠系适合于研究Fabry病的发病机制和候选疗法的临床前研究。
Fabry disease is a lysosomal storage disorder in which neutral glycosphingolipids, predominantly globotriaosylceramide (Gb3), accumulate due to deficient α-galactosidase A (α-Gal A) activity. The α-Gal A-knockout (GLAko) mouse has been used as a model for Fabry disease, but it does not have any symptomatic abnormalities. In this study, we generated a symptomatic mouse model (G3Stg/GLAko) by crossbreeding GLAko mice with transgenic mice expressing human Gb3 synthase. G3Stg/GLAko mice had high Gb3 levels in major organs, and their serum Gb3 level at 5–25 weeks of age was 6–10 times higher than that in GLAko mice of the same age. G3Stg/GLAko mice showed progressive renal impairment, with albuminuria at 3 weeks of age, decreased urine osmolality at 5 weeks, polyuria at 10 weeks, and increased blood urea nitrogen at 15 weeks. The urine volume and urinary albumin concentration were significantly reduced in the G3Stg/GLAko mice when human recombinant α-Gal A was administered intravenously. These data suggest that Gb3 accumulation is a primary pathogenic factor in the symptomatic phenotype of G3Stg/GLAko mice, and that this mouse line is suitable for studying the pathogenesis of Fabry disease and for preclinical studies of candidate therapies.