CKD (chronic kidney disease) is a life-threatening pathology, often requiring HD (haemodialysis) and characterized by high OS (oxidative stress), inflammation and perturbation of vascular endothelium. HD patients have increased levels of vWF (von Willebrand factor), a large protein (~240 kDa) released as UL-vWF (ultra large-vWF polymers, molecular mass ~20000–50000 kDa) from vascular endothelial cells and megakaryocytes, and responsible for the initiation of primary haemostasis. The pro-haemostatic potential of vWF increases with its length, which is proteolytically regulated by ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin motifs 13), a zinc-protease cleaving vWF at the single Tyr1605–Met1606 bond, and by LSPs (leucocyte serine proteases), released by activated PMNs (polymorphonuclear cells) during bacterial infections. Previous studies have shown that in vitro oxidation of Met1606 hinders vWF cleavage by ADAMTS-13, resulting in the accumulation of UL-vWF that are not only more pro-thrombotic than shorter vWF oligomers, but also more efficient in binding to bacterial adhesins during sepsis. Notably, HD patients have increased risk of developing dramatic cardiovascular and septic complications, whose underlying mechanisms are largely unknown. In the present study, we first purified vWF from HD patients and then chemically characterized its oxidative state. Interestingly, HD-vWF contains high carbonyl levels and increased proportion of UL-vWF polymers that are also more resistant to ADAMTS-13. Using TMS (targeted MS) techniques, we estimated that HD-vWF contains >10% of Met1606 in the sulfoxide form. We conclude that oxidation of Met1606, impairing ADAMTS-13 cleavage, results in the accumulation of UL-vWF polymers, which recruit and activate platelets more efficiently and bind more tightly to bacterial adhesins, thus contributing to the development of thrombotic and septic complications in CKD.
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March 2012
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Research Article|
February 13 2012
Oxidation of Met1606 in von Willebrand factor is a risk factor for thrombotic and septic complications in chronic renal failure
Vincenzo De Filippis;
Vincenzo De Filippis
1
*Laboratory of Protein Chemistry, Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
1Correspondence may be addressed to either of these authors (email vincenzo.defilippis@unipd.it or rdecristofaro@rm.unicatt.it).
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Stefano Lancellotti;
Stefano Lancellotti
†Haemostasis Research Centre, Institute of Internal Medicine and Geriatrics, Catholic University School of Medicine, Rome, Italy
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Fabio Maset;
Fabio Maset
*Laboratory of Protein Chemistry, Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
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Barbara Spolaore;
Barbara Spolaore
*Laboratory of Protein Chemistry, Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
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Nicola Pozzi;
Nicola Pozzi
2
*Laboratory of Protein Chemistry, Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
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Giovanni Gambaro;
Giovanni Gambaro
‡Division of Nephrology and Dialysis, Department of Internal Medicine and Medical Specialties, Renal Program, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy
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Laura Oggianu;
Laura Oggianu
†Haemostasis Research Centre, Institute of Internal Medicine and Geriatrics, Catholic University School of Medicine, Rome, Italy
§Section of Biology Applied to Human Health, ‘Roma Tre’ University, Rome, Italy
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Lorenzo A. Calò;
Lorenzo A. Calò
∥Department of Clinical and Experimental Medicine and Postgraduate School of Nephrology, University of Padova, Padova, Italy
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Raimondo De Cristofaro
Raimondo De Cristofaro
1
†Haemostasis Research Centre, Institute of Internal Medicine and Geriatrics, Catholic University School of Medicine, Rome, Italy
1Correspondence may be addressed to either of these authors (email vincenzo.defilippis@unipd.it or rdecristofaro@rm.unicatt.it).
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Publisher: Portland Press Ltd
Received:
October 06 2011
Revision Received:
November 15 2011
Accepted:
November 18 2011
Accepted Manuscript online:
November 18 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 442 (2): 423–432.
Article history
Received:
October 06 2011
Revision Received:
November 15 2011
Accepted:
November 18 2011
Accepted Manuscript online:
November 18 2011
Citation
Vincenzo De Filippis, Stefano Lancellotti, Fabio Maset, Barbara Spolaore, Nicola Pozzi, Giovanni Gambaro, Laura Oggianu, Lorenzo A. Calò, Raimondo De Cristofaro; Oxidation of Met1606 in von Willebrand factor is a risk factor for thrombotic and septic complications in chronic renal failure. Biochem J 1 March 2012; 442 (2): 423–432. doi: https://doi.org/10.1042/BJ20111798
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