Sex differences of urinary and kidney globotriaosylceramide and lyso-globotriaosylceramide in Fabry mice

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. We found that urine Gb3 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 Gb3 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-Gb3 concentrations were significantly higher in 12-month-old male Fabry mice than in their homozygous female counterparts. However, lyso-Gb3 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 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. 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. We found that urine Gb3 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 Gb3 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-Gb3 concentrations were significantly higher in 12-month-old male Fabry mice than in their homozygous female counterparts. However, lyso-Gb3 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 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. Fabry disease, an X-linked disorder, is associated with a widespread bodily accumulation and elevated urinary excretion of the glycosphingolipid globotriaosylceramide (Gb3) (1Schiffmann R. Fabry disease.Pharmacol. Ther. 2009; 122: 65-77Crossref PubMed Scopus (181) Google Scholar). The disease results from a deficiency of the lysosomal enzyme α-galactosidase A (2Brady R.O. Gal A.E. Bradley R.M. Martensson E. Warshaw A.L. Laster L. Enzymatic defect in Fabry disease: ceramide trihexosidase deficiency.N. Engl. J. Med. 1967; 276: 1163-1167Crossref PubMed Scopus (837) Google Scholar). The accumulation of Gb3 in humans is associated with a markedly increased risk of complications, including myriad cardiac manifestations, chronic renal insufficiency, painful small-fiber peripheral neuropathy, and cerebrovascular stroke. Despite recent advances, the mechanism by which Gb3 causes disease is still poorly understood (3Shen J.S. Meng X.L. Moore D.F. Quirk J.M. Shayman J.A. Schiffmann R. Kaneski C.R. Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells.Mol. Genet. Metab. 2008; 95: 163-168Crossref PubMed Scopus (165) Google Scholar). Levels of Gb3 in various organs, plasma, and urine have been used as markers for diagnosing patients with Fabry disease and for following the effect of specific therapy (4Schiffmann R. Kopp J.B. Austin 3rd, H.A. Sabnis S. Moore D.F. Weibel T. Balow J.E. Brady R.O. Enzyme replacement therapy in fabry disease: a randomized controlled trial.J AMA. 2001; 285: 2743-2749Crossref PubMed Scopus (1117) Google Scholar, 5Eng C.M. Banikazemi M. Gordon R.E. Goldman M. Phelps R. Kim L. Gass A. Winston J. Dikman S. Fallon J.T. et al.A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.Am. J. Hum. Genet. 2001; 68: 711-722Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar, 6Eng C.M. Guffon N. Wilcox W.R. Germain D.P. Lee P. Waldek S. Caplan L. Linthorst G.E. Desnick R.J. Safety and efficacy of recombinant human alpha-galactosidase A-replacement therapy in Fabry's disease.N. Engl. J. Med. 2001; 345: 9-16Crossref PubMed Scopus (1379) Google Scholar). A knockout mouse model of Fabry disease with a discreet phenotype that accumulates Gb3 has been described (7Ohshima T. Murray G.J. Swaim W.D. Longenecker G. Quirk J.M. Cardarelli C.O. Sugimoto Y. Pastan I. Gottesman M.M. Brady R.O. et al.alpha-Galactosidase A deficient mice: a model of Fabry disease.Proc. Natl. Acad. Sci. U SA. 1997; 94: 2540-2544Crossref PubMed Scopus (287) Google Scholar, 8Ohshima T. Schiffmann R. Murray G.J. Kopp J. Quirk J.M. Stahl S. Chan C.C. Zerfas P. Tao-Cheng J.H. Ward J.M. et al.Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice.Proc. Natl. Acad. Sci. U SA. 1999; 96: 6423-6427Crossref PubMed Scopus (86) Google Scholar, 9Ioannou Y.A. Zeidner K.M. Gordon R.E. Desnick R.J. Fabry disease: preclinical studies demonstrate the effectiveness of alpha-galactosidase A replacement in enzyme-deficient mice.Am. J. Hum. Genet. 2001; 68: 14-25Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 10Shiozuka C. Taguchi A. Matsuda J. Noguchi Y. Kunieda T. Uchio-Yamada K. Yoshioka H. Hamanaka R. Yano S. Yokoyama S. et al.Increased globotriaosylceramide levels in a transgenic mouse expressing human {alpha}1,4-galactosyltransferase and a mouse model for treating Fabry disease.J. Biochem. 2010; 149: 161-170Crossref PubMed Scopus (13) Google Scholar). This mouse model has been used for preclinical studies of new therapeutics for Fabry disease, such as enzyme replacement therapy, and for studies of Fabry disease mechanisms with outcome measurements based predominantly on measurement of Gb3 levels (11Marshall J. Ashe K.M. Bangari D. McEachern K. Chuang W.L. Pacheco J. Copeland D.P. Desnick R.J. Shayman J.A. Scheule R.K. et al.Substrate reduction augments the efficacy of enzyme therapy in a mouse model of Fabry disease.PLoS O NE. 2010; 5: e15033Crossref PubMed Scopus (59) Google Scholar, 12Choi J.O. Lee M.H. Park H.Y. Jung S.C. Characterization of Fabry mice treated with recombinant adeno-associated virus 2/8-mediated gene transfer.J. Biomed. Sci. 2010; 17: 26Crossref PubMed Scopus (16) Google Scholar, 13Ogawa K. Hirai Y. Ishizaki M. Takahashi H. Hanawa H. Fukunaga Y. Shimada T. Long-term inhibition of glycosphingolipid accumulation in Fabry model mice by a single systemic injection of AAV1 vector in the neonatal period.Mol. Genet. Metab. 2009; 96: 91-96Crossref PubMed Scopus (32) Google Scholar). However, 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 (14McCluer R.H. Williams M.A. Gross S.K. Meisler M.H. Testosterone effects on the induction and urinary excretion of mouse kidney glycosphingolipids associated with lysosomes.J. Biol. Chem. 1981; 256: 13112-13120Abstract Full Text PDF PubMed Google Scholar, 15McCluer R.H. Deutsch C.K. Gross S.K. Testosterone-responsive mouse kidney glycosphingolipids: developmental and inbred strain effects.Endocrinology. 1983; 113: 251-258Crossref PubMed Scopus (17) Google Scholar, 16Gross S.K. Daniel P.F. Evans J.E. McCluer R.H. Lipid composition of lysosomal multilamellar bodies of male mouse urine.J. Lipid Res. 1991; 32: 157-164Abstract Full Text PDF PubMed Google Scholar). Recently, these mice have been shown to accumulate deacylated Gb3, globotriaosylsphingosine (lyso-Gb3) (17Aerts J.M. Groener J.E. Kuiper S. Donker-Koopman W.E. Strijland A. Ottenhoff R. van Roomen C. Mirzaian M. Wijburg F.A. Linthorst G.E. et al.Elevated globotriaosylsphingosine is a hallmark of Fabry disease.Proc. Natl. Acad. Sci. U SA. 2008; 105: 2812-2817Crossref PubMed Scopus (514) Google Scholar). In humans, lyso-Gb3 was shown to be elevated in plasma and urine of Fabry patients and thus represents a potential new biomarker for Fabry disease (18Auray-Blais C. Ntwari A. Clarke J.T. Warnock D.G. Oliveira J.P. Young S.P. Millington D.S. Bichet D.G. Sirrs S. West M.L. et al.How well does urinary lyso-Gb3 function as a biomarker in Fabry disease?.Clin. Chim. Acta. 2010; 411: 1906-1914Crossref PubMed Scopus (87) Google Scholar). In the present study, we evaluated the concentrations of urinary and kidney Gb3 levels, as well as kidney lyso-Gb3 levels, in male and female Fabry mice, and we compared these to their respective wild-type controls. Hemizygous male and homozygous female gla knockout mice (referred to as Fabry mice; C57Bl6/SVJ129) (7Ohshima T. Murray G.J. Swaim W.D. Longenecker G. Quirk J.M. Cardarelli C.O. Sugimoto Y. Pastan I. Gottesman M.M. Brady R.O. et al.alpha-Galactosidase A deficient mice: a model of Fabry disease.Proc. Natl. Acad. Sci. U SA. 1997; 94: 2540-2544Crossref PubMed Scopus (287) Google Scholar) and wild-type control mice of the same genetic background were used. Five to eight urine samples (collected separately from each mouse) were collected from each mouse group for analysis. All specimens were collected over a 24 h duration using polycarbonate metabolic cages (model 3600M021, Tecniplast, Montreal, Quebec, Canada). Urine samples were collected at room temperature and stored at −80°C until analysis by mass spectrometry. Ten microliters of 250 ng/ml C17-Gb3 (Matreya, LLC, Pleasant Gap, PA) in methanol were added to 100 μl urine as the internal standard. Each sample was extracted with 1 ml of methanol; 5 µl of extract were injected in full loop mode in a UPLC-MS/MS system (Premier XE; Waters Corp., Milford, MA) equipped with ESI in positive ion mode (capillary 3.5 kV, cone 150 V, source 100°C, desolvation 400°C, cone gas 50 l/h, desolvation gas, 500 l/h). Eight isoforms were separated with a C18 Acquity BEH 100 × 1 mm, 1.7 µm column with a methanol/water and 0.1% formic acid step gradient. The following transitions were monitored in MRM mode: m/z 1060→898 C17-Gb3 (internal standard); m/z 1046 →884 C16, 1074→912 C18, 1102→940 C20, 1128→966 C22:1, 1130→968 C22, 1156→994 C24:1, 1158→996 C24, 1174→1012 C24OH. The ratio of the peak area sum of these eight transitions to that of the internal standard was determined. This ratio was used to calculate the total Gb3 concentration based on linear regression of the Gb3 reference standard calibration curve generated by standard addition in urine (19Auray-Blais C. Cyr D. Ntwari A. West M.L. Cox-Brinkman J. Bichet D.G. Germain D.P. Laframboise R. Melancon S.B. Stockley T. et al.Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease.Mol. Genet. Metab. 2008; 93: 331-340Crossref PubMed Scopus (87) Google Scholar). Kidney tissue was harvested from 5- and 12-month-old mice. Gb3 concentration in tissue was determined as described below. Liquid-liquid extraction with methyl tert-butyl ether followed by saponification was performed on tissue homogenate corresponding to 200 mg of total protein. Each sample was reconstituted in water/methanol 20/80 (v/v), and 5 µl were injected into a UPLC-Xevo tandem mass spectrometry system (Waters Corp.). Separation was performed on a C18 Acquity BEH 100 × 1 mm, 1.7 µm column with a methanol/water and 0.1% formic acid gradient. The following transitions were monitored in MRM mode: m/z 1046→884 C16, 1074→912 C18, 1102→940 C20, 1128→966 C22:1, 1130→968 C22, 1156→994 C24:1, 1158→996 C24, 1174→1012 C24OH. A Gb3 reference standard (Matreya) calibration curve in matching matrix prepared with the standard addition method was run in each assay for calculation of the concentration of total Gb3 in each sample. Gb3 was calculated as the sum of the concentrations of each monitored isoform. The concentration of each isoform was determined by linear regression with the internal standard. Total Gb3 was calculated using the software Targetlynx (Waters). Results were normalized to the amount of total protein (in milligrams) in each sample. Kidney tissue samples (up to 50 mg each) were prepared as previously described (20Khanna R. Soska R. Lun Y. Feng J. Frascella M. Young B. Brignol N. Pellegrino L. Sitaraman S.A. Desnick R.J. et al.The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease.Mol. Ther. 2010; 18: 23-33Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Lyso-Gb3 was assayed as previously described (18Auray-Blais C. Ntwari A. Clarke J.T. Warnock D.G. Oliveira J.P. Young S.P. Millington D.S. Bichet D.G. Sirrs S. West M.L. et al.How well does urinary lyso-Gb3 function as a biomarker in Fabry disease?.Clin. Chim. Acta. 2010; 411: 1906-1914Crossref PubMed Scopus (87) Google Scholar). α-galactosidase A activity in kidney homogenates was determined by a fluorimetric method as described previously (21Kusiak J.W. Quirk J.M. Brady R.O. Purification and properties of the two major isozymes of alpha- galactosidase from human placenta.J. Biol. Chem. 1978; 253: 184-190Abstract Full Text PDF PubMed Google Scholar). Quantitative real time RT-PCR was performed as previously described (3Shen J.S. Meng X.L. Moore D.F. Quirk J.M. Shayman J.A. Schiffmann R. Kaneski C.R. Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells.Mol. Genet. Metab. 2008; 95: 163-168Crossref PubMed Scopus (165) Google Scholar). Predesigned TaqMan probe and primers for mouse gla were purchased from Applied Biosystems, Inc. (Foster City, was used as internal control and by TaqMan probe and primers Biosystems, mRNA levels, was determined by was used for analysis of The were as the with (14McCluer R.H. Williams M.A. Gross S.K. Meisler M.H. Testosterone effects on the induction and urinary excretion of mouse kidney glycosphingolipids associated with lysosomes.J. Biol. Chem. 1981; 256: 13112-13120Abstract Full Text PDF PubMed Google Scholar, 15McCluer R.H. Deutsch C.K. Gross S.K. Testosterone-responsive mouse kidney glycosphingolipids: developmental and inbred strain effects.Endocrinology. 1983; 113: 251-258Crossref PubMed Scopus (17) Google Scholar, 16Gross S.K. Daniel P.F. Evans J.E. McCluer R.H. Lipid composition of lysosomal multilamellar bodies of male mouse urine.J. Lipid Res. 1991; 32: 157-164Abstract Full Text PDF PubMed Google urinary Gb3 levels were significantly higher in wild-type male mice compared with wild-type female mice Gb3 levels were lower in wild-type males ng/ml compared with wild-type but were to the urinary Gb3 levels in female Similarly, urinary Gb3 was significantly higher in Fabry male mice compared with homozygous Fabry female mice The urine Gb3 in Fabry homozygous females was significantly higher than in wild-type females the urine Gb3 in Fabry male mice was higher than in wild-type was not A amount of glycosphingolipid in mouse urine is from the and glycosphingolipid of urine is with that in kidney (14McCluer R.H. Williams M.A. Gross S.K. Meisler M.H. Testosterone effects on the induction and urinary excretion of mouse kidney glycosphingolipids associated with lysosomes.J. Biol. Chem. 1981; 256: 13112-13120Abstract Full Text PDF PubMed Google Scholar). We Gb3 levels in mouse and found markedly elevated Gb3 levels in males compared with females in both wild-type and Fabry mice Fabry female mice significantly higher kidney Gb3 levels compared with wild-type females In to in urine Gb3, the of kidney Gb3 in Fabry male mice compared with wild-type male mice at of was not We also was undetectable in male and female wild-type mouse However, lyso-Gb3 was in kidney of Fabry mice it was found to be significantly higher in 12-month-old male Fabry mice compared with homozygous female Fabry mice is specific isoform that predominantly to sex differences in kidney Gb3 levels, the concentration of isoforms of Gb3 were compared males and females In both wild-type and Fabry mice, isoforms C16, C22:1, and C24OHA were in males compared with females The concentration of each isoform was also compared Fabry and wild-type mice The in Fabry mouse kidney Gb3 concentration compared with wild-type was in females than in males for Gb3 isoforms This from a to concentration of Gb3 in Fabry males compared with wild-type and from a to concentration of Gb3 in Fabry females compared with wild-type Testosterone and excretion of glycosphingolipids in mouse kidney (14McCluer R.H. Williams M.A. Gross S.K. Meisler M.H. Testosterone effects on the induction and urinary excretion of mouse kidney glycosphingolipids associated with lysosomes.J. Biol. Chem. 1981; 256: 13112-13120Abstract Full Text PDF PubMed Google Scholar, 15McCluer R.H. Deutsch C.K. Gross S.K. Testosterone-responsive mouse kidney glycosphingolipids: developmental and inbred strain effects.Endocrinology. 1983; 113: 251-258Crossref PubMed Scopus (17) Google Scholar, 16Gross S.K. Daniel P.F. Evans J.E. McCluer R.H. Lipid composition of lysosomal multilamellar bodies of male mouse urine.J. Lipid Res. 1991; 32: 157-164Abstract Full Text PDF PubMed Google Scholar). levels of in male and female mice sex differences in kidney and urine the the of lysosomal such as and in murine kidney M.H. and of kidney in Biol. Chem. 1978; 253: Full Text PDF PubMed Google Scholar, K. R.E. control of induction in Biol. PubMed Scopus Google Scholar). the lysosomal of Gb3 to sex differences in kidney Gb3, we α-galactosidase A activity in kidney We found significantly lower α-galactosidase A activity in wild-type males compared with wild-type females lower enzyme activity is to lower expression of the mRNA of α-galactosidase A in kidney was by The results significantly lower mRNA in wild-type males compared with wild-type females This study shows the sex differences in kidney and urine Gb3 levels and kidney lyso-Gb3 levels in both wild-type and Fabry mice and suggests that these male-female differences should be taken into consideration when using murine models for Fabry disease. of markedly elevated urinary and kidney Gb3 in male wild-type mice compared with females (14McCluer R.H. Williams M.A. Gross S.K. Meisler M.H. Testosterone effects on the induction and urinary excretion of mouse kidney glycosphingolipids associated with lysosomes.J. Biol. Chem. 1981; 256: 13112-13120Abstract Full Text PDF PubMed Google Scholar, 15McCluer R.H. Deutsch C.K. Gross S.K. Testosterone-responsive mouse kidney glycosphingolipids: developmental and inbred strain effects.Endocrinology. 1983; 113: 251-258Crossref PubMed Scopus (17) Google Scholar, 16Gross S.K. Daniel P.F. Evans J.E. McCluer R.H. Lipid composition of lysosomal multilamellar bodies of male mouse urine.J. Lipid Res. 1991; 32: 157-164Abstract Full Text PDF PubMed Google Scholar). This is a murine as it was also present in mice and R.H. Deutsch C.K. Gross S.K. Testosterone-responsive mouse kidney glycosphingolipids: developmental and inbred strain effects.Endocrinology. 1983; 113: 251-258Crossref PubMed Scopus (17) Google Scholar). In humans, in urinary Gb3 levels was found male and female patients (19Auray-Blais C. Cyr D. Ntwari A. West M.L. Cox-Brinkman J. Bichet D.G. Germain D.P. Laframboise R. Melancon S.B. Stockley T. et al.Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease.Mol. Genet. Metab. 2008; 93: 331-340Crossref PubMed Scopus (87) Google Scholar). The male-female in Gb3 in mouse kidney is to be to increased by in male mice R.H. Deutsch C.K. Gross S.K. Testosterone-responsive mouse kidney glycosphingolipids: developmental and inbred strain effects.Endocrinology. 1983; 113: 251-258Crossref PubMed Scopus (17) Google Scholar, 16Gross S.K. Daniel P.F. Evans J.E. McCluer R.H. Lipid composition of lysosomal multilamellar bodies of male mouse urine.J. Lipid Res. 1991; 32: 157-164Abstract Full Text PDF PubMed Google Scholar). In study, we found significantly lower kidney α-galactosidase A activity in male mice compared with This suggests that the lower α-galactosidase A activity in male mouse kidney also to the higher The lower enzyme activity is at in to lower of the differences in mRNA of α-galactosidase A the that gene in mouse to the enzyme Fabry mice Gb3 accumulation in including the kidney (7Ohshima T. Murray G.J. Swaim W.D. Longenecker G. Quirk J.M. Cardarelli C.O. Sugimoto Y. Pastan I. Gottesman M.M. Brady R.O. et al.alpha-Galactosidase A deficient mice: a model of Fabry disease.Proc. Natl. Acad. Sci. U SA. 1997; 94: 2540-2544Crossref PubMed Scopus (287) Google Scholar, 8Ohshima T. Schiffmann R. Murray G.J. Kopp J. Quirk J.M. Stahl S. Chan C.C. Zerfas P. Tao-Cheng J.H. Ward J.M. et al.Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice.Proc. Natl. Acad. Sci. U SA. 1999; 96: 6423-6427Crossref PubMed Scopus (86) Google Scholar). However, our study the of sex differences in kidney and urine Gb3 and lyso-Gb3 levels in Fabry mice. The higher Gb3 in male Fabry mice than in homozygous female Fabry mice be to the of Gb3 in is that in Gb3 in male Fabry mice be by α-galactosidase A of therapy T. Schiffmann R. Murray G.J. Kopp J. Quirk J.M. Stahl S. Chan C.C. Zerfas P. Tao-Cheng J.H. Ward J.M. et al.Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice.Proc. Natl. Acad. Sci. U SA. 1999; 96: 6423-6427Crossref PubMed Scopus (86) Google Scholar, 9Ioannou Y.A. Zeidner K.M. Gordon R.E. Desnick R.J. Fabry disease: preclinical studies demonstrate the effectiveness of alpha-galactosidase A replacement in enzyme-deficient mice.Am. J. Hum. Genet. 2001; 68: 14-25Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 13Ogawa K. Hirai Y. Ishizaki M. Takahashi H. Hanawa H. Fukunaga Y. Shimada T. Long-term inhibition of glycosphingolipid accumulation in Fabry model mice by a single systemic injection of AAV1 vector in the neonatal period.Mol. Genet. Metab. 2009; 96: 91-96Crossref PubMed Scopus (32) Google Scholar, T. Murray G.J. G. Quirk J.M. T. P. K. Brady R.O. J.A. Long-term enzyme and reduction in of and Fabry mice bone marrow Natl. Acad. Sci. U SA. PubMed Scopus Google Scholar, J. Murray G.J. A. Quirk J.M. Brady R.O. P. Long-term of globotriaosylceramide in Fabry mice by recombinant adeno-associated gene Natl. Acad. Sci. U SA. PubMed Scopus Google Scholar). it that the Gb3 is to of the deficient the sex in total Gb3 levels in isoform analysis that the of each isoform is also sex Isoforms C16, C22:1, and C24OHA were significantly higher in males in both wild-type and Fabry mice, that these isoforms be et that of the two Gb3 of Fabry mouse kidney extract in does not to enzyme Y.A. Zeidner K.M. Gordon R.E. Desnick R.J. Fabry disease: preclinical studies demonstrate the effectiveness of alpha-galactosidase A replacement in enzyme-deficient mice.Am. J. Hum. Genet. 2001; 68: 14-25Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). is that the isoforms described be the major of the Gb3 In is an of ratio of Gb3 in Fabry mice compared with 5 of This is to a Gb3 accumulation in the female Fabry mice Despite the accumulation of Gb3 and lyso-Gb3 in kidney of Fabry mice shown in study and (17Aerts J.M. Groener J.E. Kuiper S. Donker-Koopman W.E. Strijland A. Ottenhoff R. van Roomen C. Mirzaian M. Wijburg F.A. Linthorst G.E. et al.Elevated globotriaosylsphingosine is a hallmark of Fabry disease.Proc. Natl. Acad. Sci. U SA. 2008; 105: 2812-2817Crossref PubMed Scopus (514) Google Scholar) and the in kidney T. Schiffmann R. Murray G.J. Kopp J. Quirk J.M. Stahl S. Chan C.C. Zerfas P. Tao-Cheng J.H. Ward J.M. et al.Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice.Proc. Natl. Acad. Sci. U SA. 1999; 96: 6423-6427Crossref PubMed Scopus (86) Google Scholar, 10Shiozuka C. Taguchi A. Matsuda J. Noguchi Y. Kunieda T. Uchio-Yamada K. Yoshioka H. Hamanaka R. Yano S. Yokoyama S. et al.Increased globotriaosylceramide levels in a transgenic mouse expressing human {alpha}1,4-galactosyltransferase and a mouse model for treating Fabry disease.J. Biochem. 2010; 149: 161-170Crossref PubMed Scopus (13) Google clinical such as and renal which in Fabry in Fabry mice. A of kidney phenotype in Fabry mice including potential sex differences in these is in The of Gb3 to total Gb3, and in Fabry mouse kidney not However, of Gb3 the α-galactosidase A activity and Gb3 in kidney of male Fabry mice. study suggests that at Gb3 levels in kidney urine as an outcome for preclinical studies new female homozygous mice should be the model to it is and and

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