Depletion of globosides and isoglobosides fully reverts the morphologic phenotype of Fabry disease.

Abstract

Fabry disease is a monogenic X-linked lysosomal storage disease caused by α-galactosidase A (αGalA) deficiency. Enzyme replacement therapy through administration of the missing αGalA is currently the only accepted therapeutic option. However, this treatment is connected to high costs, has ill-defined indication criteria and its efficacy is controversially discussed. Our aim was to explore the possibility of a novel targeted substrate reduction therapy for Fabry disease. Owing to the fact that αGalA-deficient humans and mice accumulate the same glycosphingolipids (i.e. globosides, galabiosylceramide and isoglobosides), αGalA-deficient mice were crossed with mice deficient in enzymes synthesizing these classes of glycosphingolipids (i.e. globotrihexosylceramide and isoglobotrihexosylceramide synthase, respectively). Functional heart and kidney tests were performed together with an extensive biochemical analysis of urine and serum in aged mice. Lysosomal storage was assessed by thin layer chromatography and electron microscopy. We showed that depletion of globosides was sufficient to fully abolish the storage of glycosphingolipids in heart, kidney and liver and was paralleled by a complete restoration of lysosomal morphology in these organs. In contrast, in dorsal root ganglia, a depletion of both globosides and isoglobosides was necessary to fully counteract the lysosomal storage. The deficiency in globosides and/or isoglobosides did not cause any adverse effects. We conclude that substrate reduction therapy through inhibition of the synthesis of globosides and isoglobosides represents a valuable therapeutic option for Fabry disease, all the more as globosides and isoglobosides seem to be dispensable.Electronic supplementary materialThe online version of this article (doi:10.1007/s00441-014-1922-9) contains supplementary material, which is available to authorized users.

Renal globotriaosylceramide facilitates tubular albumin absorption and its inhibition protects against acute kidney injury

“…GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; Gb4, globotetraosylceramide. (Gb3S À/À ) 13 ; the mouse is an ideal model for the analysis of tubular function of Gb3 because we, in accordance with other groups, now have proven that Gb3 is not expressed in murine glomeruli but only in renal tubules. 5,14 Our results show an involvement of Gb3 in the reabsorption of proteins and xenobiotics by PTECs; Gb3 abolishment, which can be partially achieved by pharmacologic treatment with GENZ-123346, protects against myoglobin-induced AKI and also shows a decrease in gentamicin-induced AKI.…”

Direct acute tubular damage contributes to Shigatoxin‐mediated kidney failure

“…As shown by others and ourselves, in the kidneys of WT mice, Gb3 expression is limited to collecting ducts but is absent from renal endothelial cells (Figure ; see also supplementary material, Figures S1, S2 ). The lack of Gb3 in murine renal endothelium and its pure tubule‐specific expression are further supported by the facts that: (a) in mice with Fabry disease (lysosomal storage disease characterized by defective degradation of Gb3), no Gb3 accumulates in renal endothelial cells ; and (b) no residual Gb3 is present in murine kidneys when genetically depleting it from tubular cells .…”

Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie-restricted mice

“…However, enlarged structures consisting of multiple concentrically arranged electron‐dense lamella occupying a high proportion of cellular volume were mainly found in PCT cells from old control and CRF‐fed mice. Nearly identical structures have been reported in a C57BL/6 mouse model of accelerated renal senescence (Yumura et al ., 2006) and in other murine models with defective lysosomal activity (Porubsky et al ., 2014). These authors identify these structures as lysosomes with accumulated lipofuscin and perhaps other nondegradable pigments, an idea compatible with the well‐known fact that PCT cells may accumulate lipofuscin during aging (Melk et al ., 2003).…”