4.7 Article

-Galactosidase A-deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease

Journal

FASEB JOURNAL
Volume 33, Issue 1, Pages 418-429

Publisher

FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201800771R

Keywords

lysosomal storage disease; glycobiology; kidney; heart; animal model

Funding

  1. U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases [R01DK042667]
  2. NIH National Institute of Neurological Disorders and Stroke [R21NS095627]
  3. NIH National Institute of Allergy and Infectious Diseases [R21AI129873]
  4. NIH National Institute of General Medical Sciences [P41GM103490]
  5. NIH National Institute of Diabetes and Digestive and Kidney Diseases [F30DK113641]
  6. NIH National Heart, Lung, and Blood Institute [R24HL114474]
  7. [T32GM080202]

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Fabry disease is an X-linked lysosomal storage disease caused by -galactosidase A (-Gal A) deficiency. Kidney and heart failure are frequent complications in adulthood and greatly contribute to patient morbidity and mortality. Because -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 -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., -Galactosidase A-deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease.

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