title: [Globosides as key players in the pathophysiology of Shiga toxin-associated acute kidney failure and Fabry disease].
abstract: Globosides and their isomeric counterparts isoglobosides belong to the class of neutral glycosphingolipids with an as yet undefined physiological function. In the pathogenesis of human diseases, globosides play an important role as cellular receptors for Shiga toxins which are produced by certain strains of S. dysenteriae and E. coli. In order to elucidate the pathogenesis of Shiga toxin-associated kidney failure, we studied human kidney biopsies and animal models. Our work showed that in patients suffering from Shiga toxin-elicited kidney failure, no complement activation could be demonstrated by immunohistochemical analysis of kidney biopsies. Therefore, complement activation is unlikely to play a major role in mediating thrombotic microangiopathy on exposure to Shiga toxin. Moreover, analysis of the human biopsies and of a murine model of Shiga toxin-associated disease pinpointed acute tubular damage as an important and previously neglected contributor to acute kidney failure in patients infected with Shiga toxin-producing E. coli. Furthermore, globosides play a decisive role in the pathogenesis of Fabry disease which results from a decreased or absent activity of the lysosomal enzyme α-galactosidase A. The results on transgenic mice showed that in vital organs, such as the heart, kidneys and liver, it was possible to revert the phenotype of Fabry disease by eliminating the synthesis of globosides. This implicates that substrate reduction therapy through inhibition of globosides might represent a new therapeutic option for Fabry disease, all the more so as globosides seem to be dispensable.
authors.affiliation: Zelluläre und Molekulare Pathologie , Deutsches Krebsforschungszentrum, Heidelberg, Deutschland, s.porubsky@dkfz.de.
authors.forename: S
authors.initials: S
authors.lastname: Porubsky
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001706:Biopsy; D003167:Complement Activation / Q000502:physiology; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000473:pathology / Q000503:physiopathology*; D005915:Globosides / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007684:Kidney Tubules / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D022621:Shiga Toxin; D054323:Shiga-Toxigenic Escherichia coli / Q000472:pathogenicity; D057049:Thrombotic Microangiopathies / Q000473:pathology / Q000503:physiopathology; D000519:alpha-Galactosidase / Q000502:physiology
chemical_list: D005915:Globosides; D022621:Shiga Toxin; D000519:alpha-Galactosidase