Lysosomal sulfoglycolipid storage in the kidneys of mice deficient for arylsulfatase A (ASA) and of double-knockout mice deficient for ASA and galactosylceramide synthase

The inherited deficiency of arylsulfatase A (ASA) causes lysosomal accumula tion of sulfoglycolipids (mainly sulfo-galactosylceramide, S-GalCer) and le ads to metachromatic leukodystrophy in humans. Among visceral organs, kidne ys are particularly affected. In the present study, the regional distributi on and temporal development of sulfoglycolipid storage in kidneys of ASA(-/ -) mice was investigated histochemically (alcian blue) and ultrastructurall y. Furthermore, the sulfoglycolipid storage was examined in kidneys of doub le-knockout mice, which are incapable of: (a) degrading any sulfolipids (AS A-/-) and (b) synthesizing the major sulfo-lipid S-GalCer because of defici ency for galactosylceramide synthase (CGT), with the aim to search for addi tional ASA substrates. In ASA-/- mice, the nephron segments could be ranged in the order of decreasing sulfolipid storage: thin limbs of long-looped n ephrons similar to thick ascending limbs > distal convoluted tubules > coll ecting ducts similar to short thin limbs. Macula densa and proximal tubules were unaffected. In ASA(-/-)/CGT(-/-) mice, the long thin limbs and distal convoluted tubules resembled those of ASA(-/-)/CGT(+/+) mice, while the ot her segments showed less storage. The results suggest that the turnover of sulfolipids in general is highest in the distal nephron except macula densa , and that long thin limbs and distal convoluted tubules are the main sites for turnover of a minor sulfolipid species, which is known to be synthesiz ed in the kidney of CGT(-/-) mice.