Kidney lipids in galactosylceramide synthase-deficient mice: absence of galactosylsulfatide and compensatory increase in more polar sulfoglycolipids

Keiko Tadano-Aritomi,Toshiyuki Hikita,Hirokazu Fujimoto,Kunihiko Suzuki,Kohji Motegi,Ineo Ishizuka

doi:10.1016/s0022-2275(20)33431-3

Abstract

UDP-galactose:ceramide galactosyltransferase (CGT) catalyzes the final step in the synthesis of galactosylceramide (GalCer). It has previously been shown that CGT-deficient mice do not synthesize GalCer and its sulfated derivative GalCer I(3)-sulfate (galactosylsulfatide, SM4s) but form myelin containing glucosylceramide (GlcCer) and sphingomyelin with 2-hydroxy fatty acids. Because relatively high concentrations of GalCer and SM4s are present also in mammalian kidney, we analyzed the composition of lipids in the kidney of Cgt(-/-) and, as a control, Cgt(+/-) and wild-type mice. The homozygous mutant mice lacked GalCer, galabiaosylceramide (Ga(2)Cer), and SM4s. Yet, they did not show any major morphological or functional defects in the kidney. A slight increase in GlcCer containing 4-hydroxysphinganine was evident among neutral glycolipids. Intriguingly, more polar sulfoglycolipids, that is, lactosylceramide II(3)-sulfate (SM3) and gangliotetraosylceramide II(3),IV(3)-bis-sulfate (SB1a), were expressed at 2 to 3 times the normal levels in Cgt(-/-) mice, indicating upregulation of biosynthesis of SB1a from GlcCer via SM3. Given that SM4s is a major polar glycolipid constituting renal tubular membrane, the increase in SM3 and SB1a in the mice deficient in CGT and thus SM4s appears to be a compensatory process, which could partly restore kidney function in the knockout mice.

Highlights

UDP-galactose:ceramide galactosyltransferase (CGT) catalyzes the final step in the synthesis of galactosylceramide (GalCer)
To examine the renal function of CgtϪ/Ϫ mice, several parameters including blood urea nitrogen (BUN), creatinine, Naϩ, Kϩ, ClϪ, urinary osmolality, and ␤-N-acetyl-d-glucosaminidase (NAG) excretion were measured in serum or urine samples
Transcripts of the Cgt gene were clearly detected in the normal kidney [28] and testis [29, 30] in addition to the cerebrum and cerebellum, suggesting that the loss of this enzyme activity may affect the function of these tissues and contribute to the phenotype of the mutants

Summary

Introduction

UDP-galactose:ceramide galactosyltransferase (CGT) catalyzes the final step in the synthesis of galactosylceramide (GalCer). Because relatively high concentrations of GalCer and SM4s are present in mammalian kidney, we analyzed the composition of lipids in the kidney of Cgt؊/؊ and, as a control, Cgtϩ/؊ and wildtype mice. The homozygous mutant mice lacked GalCer, galabiaosylceramide (Ga2Cer), and SM4s. They did not show any major morphological or functional defects in the kidney. Given that SM4s is a major polar glycolipid constituting renal tubular membrane, the increase in SM3 and SB1a in the mice deficient in CGT and SM4s appears to be a compensatory process, which could partly restore kidney function in the knockout mice.—Tadano-Aritomi, K., T. Kidney lipids in galactosylceramide synthase-deficient mice: absence of galactosylsulfatide and compensatory increase in more polar sulfoglycolipids.

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Conclusion