Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
FASEB J. 2019 Jan;33(1):418-429. doi: 10.1096/fj.201800771R. Epub 2018 Jul 6.
Fabry disease is an X-linked lysosomal storage disease caused by α-galactosidase A (α-Gal A) deficiency. Kidney and heart failure are frequent complications in adulthood and greatly contribute to patient morbidity and mortality. Because α-Gal A-deficient mouse models do not recapitulate cardiorenal findings observed in patients, a nonmouse model may be beneficial to our understanding of disease pathogenesis. In this study, we evaluated disease processes in a recently generated Fabry rat model. We found that male Fabry rats weighed significantly less than wild-type (WT) males, whereas female Fabry rats weighed significantly more than WT females. Whereas no difference in female survival was detected, we observed that male Fabry rats had a decreased lifespan. Skin histology revealed that inflammation and lipoatrophy may be chief disease mediators in patients. With respect to the kidney and heart, we found that both organs accumulate α-Gal A substrates, including the established biomarkers, globotriaosylceramide and globotriaosylsphingosine. Longitudinal serum and urine chemistry panels demonstrated pronounced renal tubule dysfunction, which was confirmed histologically. Mitral valve thickening was observed in Fabry rats using echocardiography. We conclude that Fabry rats recapitulate important kidney and heart phenotypes experienced by patients and can be further used to study disease mechanisms and test therapies.-Miller, J. J., Aoki, K., Mascari, C. A., Beltrame, A. K., Sokumbi, O., North, P. E., Tiemeyer, M., Kriegel, A. J., Dahms, N. M., α-Galactosidase A-deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease.
法布里病是一种 X 连锁溶酶体贮积病，由α-半乳糖苷酶 A（α-Gal A）缺乏引起。肾脏和心力衰竭是成年期常见的并发症，极大地增加了患者的发病率和死亡率。由于缺乏α-Gal A 的小鼠模型不能重现患者中观察到的心肾发现，因此非小鼠模型可能有助于我们了解疾病的发病机制。在这项研究中，我们评估了最近生成的法布里大鼠模型中的疾病过程。我们发现，雄性法布里大鼠的体重明显低于野生型（WT）雄性大鼠，而雌性法布里大鼠的体重明显高于 WT 雌性大鼠。虽然未发现雌性生存率的差异，但我们观察到雄性法布里大鼠的寿命缩短。皮肤组织学显示，炎症和脂肪萎缩可能是患者的主要疾病介质。就肾脏和心脏而言，我们发现这两个器官都积累了α-Gal A 底物，包括已建立的生物标志物，神经节苷脂和神经节苷脂鞘氨醇。纵向血清和尿液化学小组表明，存在明显的肾小管功能障碍，这在组织学上得到了证实。使用超声心动图观察到法布里大鼠的二尖瓣增厚。我们得出结论，法布里大鼠重现了患者经历的重要肾脏和心脏表型，并且可以进一步用于研究疾病机制和测试疗法。-米勒，J. J.，青木，K.，马斯卡里，C. A.，贝尔特拉梅，A. K.，索昆比，O.，北，P. E.，蒂梅耶，M.，克里格尔，A. J.，达姆斯，N. M.，α-半乳糖苷酶 A 缺乏的大鼠积累糖脂并发展法布里病的心脏肾脏表型。
