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Verocytotoxin inhibits mitogenesis and protein synthesis in purified human glomerular mesangial cells without affecting cell viability: evidence for two distinct mechanisms.

P A Van Setten, V W van Hinsbergh, L P Van den Heuvel, T J van der Velden, N C van de Kar, R J Krebbers, M A Karmali and L A Monnens
JASN December 1997, 8 (12) 1877-1888; DOI: https://doi.org/10.1681/ASN.V8121877
P A Van Setten
Department of Pediatrics, University Hospital, Nijmegen, The Netherlands.
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V W van Hinsbergh
Department of Pediatrics, University Hospital, Nijmegen, The Netherlands.
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L P Van den Heuvel
Department of Pediatrics, University Hospital, Nijmegen, The Netherlands.
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T J van der Velden
Department of Pediatrics, University Hospital, Nijmegen, The Netherlands.
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N C van de Kar
Department of Pediatrics, University Hospital, Nijmegen, The Netherlands.
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R J Krebbers
Department of Pediatrics, University Hospital, Nijmegen, The Netherlands.
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M A Karmali
Department of Pediatrics, University Hospital, Nijmegen, The Netherlands.
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L A Monnens
Department of Pediatrics, University Hospital, Nijmegen, The Netherlands.
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Abstract

Acute renal failure is one of the hallmarks of the hemolytic uremic syndrome (HUS). Infection with a verocytotoxin (VT)- or Shiga-like toxin (SLT)-producing Escherichia coli has been strongly implicated in the etiology of the epidemic form of HUS. The functional receptor for these closely related toxins appears to be a glycosphingolipid, globotriaosylceramide (Gb3). Endothelial damage in the glomeruli and arterioles of the kidney induced by VT is believed to play a crucial role in the pathogenesis of HUS. However, little information is available regarding the effects of VT on mesangial cells, which also play an important role in glomerular function. In this study, the effects of VT on human mesangial cells in vitro were investigated. Mesangial cells were enriched by collecting hillock-shaped outgrowths derived from adult human glomeruli and subsequently purified by elimination of contaminating epithelial cells by immunoseparation with ulex europaeus lectin-I (UEA-I)-coated dynabeads. The obtained and subcultured mesangial cell populations were >98% pure. Their mesangial nature was established by the presence of a-smooth muscle cell actin in highly confluent cultures and the absence of cytokeratin or platelet/endothelial cell adhesion molecule-1. Mesangial cells bound VT to bands of Gb3 and a closely related glycolipid, which is similar to a glycolipid involved in the VT-dependent cytokine production in monocytes. VT did not induce the release of cytokines or chemokines in mesangial cells. In VT-susceptible cells, binding of VT to Gb3 causes cell death by the inhibition of protein synthesis. Although protein synthesis was inhibited in mesangial cells, all cells remained viable, both under basal and tumor necrosis factor-alpha-stimulated conditions. However, the marked reduction in protein synthesis may impair a proper response of the cells in conditions of increased demand of newly synthesized proteins. Furthermore, VT markedly inhibited DNA synthesis and proliferation of mesangial cells. The inhibition of mitogenesis was also found with the B-subunit of VT-1 alone, albeit to a lesser extent, without a significant effect on protein synthesis. Because the inhibition of protein synthesis involves the A-subunit, this suggests that two distinct mechanisms contribute to the effects of VT on protein synthesis and mitogenesis. Intracellular routing of VT (A- and B-subunits) may vary between cell types and result in differential effects on human mesangial cells when compared with other cell types.

  • Copyright © 1997 by American Society of Nephrology
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Journal of the American Society of Nephrology
Vol. 8, Issue 12
1 Dec 1997
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Verocytotoxin inhibits mitogenesis and protein synthesis in purified human glomerular mesangial cells without affecting cell viability: evidence for two distinct mechanisms.
P A Van Setten, V W van Hinsbergh, L P Van den Heuvel, T J van der Velden, N C van de Kar, R J Krebbers, M A Karmali, L A Monnens
JASN Dec 1997, 8 (12) 1877-1888; DOI: 10.1681/ASN.V8121877

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Verocytotoxin inhibits mitogenesis and protein synthesis in purified human glomerular mesangial cells without affecting cell viability: evidence for two distinct mechanisms.
P A Van Setten, V W van Hinsbergh, L P Van den Heuvel, T J van der Velden, N C van de Kar, R J Krebbers, M A Karmali, L A Monnens
JASN Dec 1997, 8 (12) 1877-1888; DOI: 10.1681/ASN.V8121877
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Cited By...

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  • Verocytotoxin-Induced Apoptosis of Human Microvascular Endothelial Cells
  • Bcl-2 antiapoptotic protein mediates verotoxin II-induced cell death: possible association between Bcl-2 and tissue failure by E. coli O157:H7
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