Abstract
The aim of our study was to measure globotriaosylceramide (Gb(3)) and lyso-Gb(3) levels by tandem mass spectrometry in the urine and kidney in Fabry (gla knockout) mice and wild-type controls. We found that urine Gb(3) of male and female Fabry mice was higher than wild-type mice of the same sex but also significantly higher in male mice compared with females of the same genotype. In kidney tissue, sex and genotype-dependent differences in Gb(3) levels paralleled those in the urine. Isoforms C16, C22:1, and C24OHA were particularly higher in males compared with females in both wild-type and Fabry mice. Similarly, kidney lyso-Gb(3) concentrations were significantly higher in 12-month-old male Fabry mice than in their homozygous female counterparts. However, lyso-Gb(3) was undetectable in wild-type mice of both sexes. α-Galactosidase A activity and mRNA levels in kidney were significantly lower in male wild-type mice compared with female mice. This study shows the sex differences in kidney and urine Gb(3) and kidney lyso-Gb(3) levels in both wild-type and Fabry mice, and it suggests that these male-female differences should be taken into consideration when using murine models for Fabry disease.
Highlights
The aim of our study was to measure globotriaosylceramide (Gb3) and lyso-Gb3 levels by tandem mass spectrometry in the urine and kidney in Fabry mice and wild-type controls
Urinary Gb3 levels were lower in prepubertal wild-type males [399 ± 31 ng/ml (n = 3)] compared with adult wild-type males, but they were similar to the urinary Gb3 levels measured in one prepubertal female (255 ng/ml)
A considerable amount of glycosphingolipid in mouse urine is excreted from the kidney, and glycosphingolipid content of urine is correlated with that in kidney tissues [14]
Summary
The aim of our study was to measure globotriaosylceramide (Gb3) and lyso-Gb3 levels by tandem mass spectrometry in the urine and kidney in Fabry (gla knockout) mice and wild-type controls. This study shows the sex differences in kidney and urine Gb3 and kidney lyso-Gb3 levels in both wild-type and Fabry mice, and it suggests that these male-female differences should be taken into consideration when using murine models for Fabry disease.—Durant, B., S. The concentrations of urinary Gb3 in the Fabry mouse model have not been described and little attention has been paid to the male versus female murine Gb3 levels in wild-type and knockout Fabry mice [14,15,16]. These mice have been shown to accumulate deacylated Gb3, globotriaosylsphingosine (lyso-Gb3) [17]. Mice Hemizygous male and homozygous female gla knockout mice (referred to as Fabry mice; C57Bl6/SVJ129) [7] and wildtype control mice of the same genetic background were used
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