Shiga toxin-2 results in renal tubular injury but not thrombotic microangiopathy in heterozygous factor H-deficient mice.
Haemolytic uraemic syndrome (HUS) is characterized by microangiopathic haemolytic anaemia, thrombocytopenia and renal failure because of thrombotic microangiopathy (TMA). It may be caused by infection with Shiga toxin-producing enteropathic bacteria (Stx-associated HUS) or with genetic defects in complement alternative pathway (CAP) regulation (atypical HUS). We hypothesized that defective complement regulation could increase host susceptibility to Stx-associated HUS. Hence, we studied the response of mice with heterozygous deficiency of the major CAP regulator, factor H, to purified Stx-2. Stx-2 was administered together with lipopolysaccharide to wild-type and Cfh(+/-) C57BL/6 animals. Forty-eight hours after administration of the first Stx-2 injection all animals developed significant uraemia. Renal histology demonstrated significant tubular apoptosis in the cortical and medullary areas which did not differ between wild-type or Cfh(+/-) Stx-2-treated mice. Uraemia and renal tubular apoptosis did not develop in wild-type or Cfh(+/-) animals treated with lipopolysaccharide alone. No light microscopic evidence of TMA or abnormal glomerular C3 staining was demonstrable in the Stx-2 treated animals. In summary, Stx-2 administration did not result in TMA in either Cfh(+/-) or wild-type C57BL/6 mice. Furthermore, haploinsufficiency of factor H did not alter the development of Stx-2-induced renal tubular injury.
Paixão-Cavalcante
D
D
Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK.
Botto
M
M
Cook
H T
HT
Pickering
M C
MC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017242:Complement Factor H / Q000172:deficiency*; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022641:Shiga Toxin 2 / Q000633:toxicity*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D014511:Uremia / Q000139:chemically induced
D008070:Lipopolysaccharides; D022641:Shiga Toxin 2; D017242:Complement Factor H