Enterococci are dangerous opportunistic pathogens with the potential to cause life-threatening infections due in part to their intrinsic resistance to cephalosporin antibiotics. Elucidating the molecular mechanisms that provide this resistance is critical for the development of strategies to both prevent and treat enterococcal infections.
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.
plated at sub-confluence, then irradiated using a cesium irradiator. Senescence was determined by chromogenic beta-galactosidase assay (percent positive b-gal). 129Sv+/+ and 129Sv Fanca-/-mice received total body irradiation (TBI) using a Mark I Gamma Cell Irradiator. Subgroups of TBI and control mice were maintained on regular water or with 400uM MMS350 (Kalash, et al., Radiat Res, 180:474, 2013). Subgroups were sacrificed at 7days or 1 year after irradiation. Organs were immediately sectioned and scored for b-gal at 40x magnification. Statistical analysis was carried out using student's t-test. Results: Control non-irradiated cells showed no significant effect of genotype on senescence-associated b-gal staining at baseline (0.23% +/-0.23% in WT vs 0.23% +/-0.23% in Fanca-/-). By day 3 after 10Gy, b-gal staining was significantly induced in both WT (3.06% +/-1.08%, pZ0.007) and Fanca-/-cell lines (10.5% +/-1.17%, pZ0.001). Fanca-/showed significantly higher induction compared to WT (p<0.0001). Growth in MMS350 after 10Gy reduced senescence in Fanca-/-cell lines (8.12% +/-1.2%, pZ0.04). Seven days after 7Gy TBI, the spleen showed a significant increase in b-gal staining in both WT (0.74 +/-0.07 at 0Gy vs 1.81 +/-0.39 at 7Gy, pZ0.020) and in Fanca-/-(0.38 +/-0.20 at 0Gy vs 1.5 +/-0.45 at 7Gy, pZ0.029). At 1 year, WT showed a higher baseline staining compared to Fanca-/-in spleen (1.43 +/-0.10 in WT vs 0.83 +/-0.14 in Fanca-/-, pZ0.025). In contrast, 7.5 Gy caused a significant decrease in b-gal in WT at 1 yr (0.81 +/-0.12, pZ0.036) with little effect of MMS350. In Fanca-/-spleen, there was an increase at 1 yr (1.58 +/-0.13 after 7.5 Gy, pZ0.0009), which was reduced by MMS350 (1.17 +/-0.13). The brain showed no significant effect of time or genotype between groups. Conclusion: Fanca-/-bone marrow stromal cell lines showed greater irradiation induction of senescence over time compared to WT. MMS350 caused a reduction in the senescence in Fanca-/-. In vivo, the spleen showed a significant radiation induction in Fanca-/-and WT at 7 days. In contrast, WT spleen showed decreased senescence at 1 year after irradiation, while Fanca-/-spleen showed an increase. In the Fanca-/-mice, MMS350 reduced senescence at 1 year after irradiation.
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