Molecular basis for high renal cell sensitivity to the cytotoxic effects of shigatoxin-1: upregulation of globotriaosylceramide expression. Academic Article uri icon

Overview

abstract

  • Cellular injury in post-diarrheal hemolytic-uremic syndrome (D+HUS) is related to shigatoxin (Stx) binding to globotriaosylceramide (Gb3). High renal Gb3 expression may determine renal susceptibility in D+HUS; however, the molecular mechanism(s) responsible for such relatively abundant Gb3 levels are unknown. Consequently, kidney cells expressing high Gb3 (cultured human proximal tubule cells [HPT]) were compared with non-kidney cells with low Gb3 content (cultured human brain microvascular endothelial cells [HBEC]). HPT were much more sensitive to the cytotoxic and protein synthesis inhibitory effects of Stx-1; this correlated with Gb3 content and (125)I-Stx-1 binding. HPT had greater Gb3 synthase (GalT6) and lower alpha-galactosidase activities than HBEC, whereas lactosylceramide synthase (GalT2) activity was higher in HBEC. Ceramide glucosyltransferase (CGT) activity was similar between the two cell types. The higher HPT GalT6 activity was associated with increased GalT6 mRNA steady-state levels, but no difference in GalT6 mRNA half-life. The lower HPT alpha-galactosidase activity was associated with reduced alpha-galactosidase mRNA steady-state levels but no difference in alpha-galactosidase mRNA half-life. Higher HBEC GalT2 activity was associated with increased steady-state GalT2 mRNA levels. These studies suggest that high renal Gb3 expression is due to enhanced GalT6 gene transcription and reduced alpha-galactosidase gene transcription and occur despite relatively low GalT2 activity.

publication date

  • September 1, 2002

Research

keywords

  • Endothelium, Vascular
  • Kidney Tubules, Proximal
  • Shiga Toxin 1
  • Trihexosylceramides

Identity

Scopus Document Identifier

  • 0036707878

Digital Object Identifier (DOI)

  • 10.1097/01.asn.0000027873.85792.52

PubMed ID

  • 12191968

Additional Document Info

volume

  • 13

issue

  • 9