ABSTRACT
The binding of Shiga-like toxins (Stx) to globotriaosyl ceramide (Gb(3)) in renal cells plays a central role in Stx-induced hemolytic uremic syndrome (Stx-HUS). Khan et al. show that the presence of Gb(3) within lipid raft microdomains in glomerular but not tubular cells may be the basis for the glomerular- and age-restricted pathology of Stx-HUS. They also propose that the binding of the HIV-1 glycoprotein gp120 to Gb(3) in renal tubules may play a role in HIV nephropathy.
Subject(s)
Glycosphingolipids/metabolism , HIV-1/pathogenicity , Kidney/metabolism , Membrane Microdomains/metabolism , Shiga Toxins/pharmacokinetics , AIDS-Associated Nephropathy/etiology , HIV Envelope Protein gp120/pharmacokinetics , HIV-1/chemistry , Hemolytic-Uremic Syndrome/etiology , Humans , Kidney/pathology , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Kidney Tubules/metabolism , Kidney Tubules/pathology , Membrane Microdomains/virology , Permeability , Protein Binding , Protein Synthesis Inhibitors/pharmacokinetics , Protein TransportABSTRACT
Verotoxin binding to its receptor, globotriaosyl ceramide(Gb(3)) mediates the glomerular pathology of hemolytic uremic syndrome, but Gb(3) is expressed in both tubular and glomerular cells. Gb(3) within detergent-resistant membranes, an index of glycolipid-cholesterol enriched lipid rafts, is required for in vitro cytotoxicity. We found that verotoxin 1 and 2 binding to human adult renal glomeruli is detergent resistant, whereas the strong verotoxin binding to renal tubules is detergent sensitive. Verotoxin binding to pediatric glomeruli was detergent resistant but binding to adult glomeruli was enhanced, remarkably for some samples, by detergent extraction. Detergent-sensitive glomerular components may provide age-related protection against verotoxin glomerular binding. Mouse glomeruli remained verotoxin unreactive after detergent extraction, whereas tubular binding was lost. Cholesterol extraction induced strong verotoxin binding in poorly reactive adult glomeruli, suggesting cholesterol can mask Gb(3) in glomerular lipid rafts. Binding of the human immunodeficiency virus (HIV) adhesin, gp120 (another Gb(3) ligand) was detergent sensitive, tubule-restricted, and inhibited by verotoxin B subunit pretreatment, and may relate to HIV nephropathy. Our study shows that differential membrane Gb(3) organization in glomeruli and tubules provides a basis for the age- and glomerular-restricted pathology of hemolytic uremic syndrome.
