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The Role of the N-Terminal Domain of Thrombomodulin and the Potential of Recombinant Human Thrombomodulin as a Therapeutic Intervention for Shiga Toxin-Induced Hemolytic-Uremic Syndrome Kröller, Sarah; Schober, Jana; Krieg, Nadine; Dennhardt, Sophie; Pirschel, Wiebke; Kiehntopf, Michael; Conway, Edward M.; Coldewey, Sina M.
Abstract
Hemolytic-uremic syndrome (HUS) is a rare complication of an infection with Shiga toxin (Stx)-producing Escherichia coli (STEC-HUS), characterized by severe acute kidney injury, thrombocytopenia and microangiopathic hemolytic anemia, and specific therapy is still lacking. Thrombomodulin (TM) is a multi-domain transmembrane endothelial cell protein and its N-terminal domain has been implicated in the pathophysiology of some cases of HUS. Indeed, the administration of recombinant human TM (rhTM) may have efficacy in HUS. We used a Stx-based murine model of HUS to characterize the role of the N-terminal domain of TM. We show that mice lacking that domain (TMLed (−/−)) are more sensitive to Stx, with enhanced HUS progression seen at 4 days and increased mortality at 7 days post-HUS induction. In spite of these changes, renal function was less affected in surviving Stx-challenged TMLed (−/−) mice compared to their wild-type counterparts TMLed (+/+) at 7 days. Contrary to few clinical case reports from Japan, the administration of rhTM (0.06 mg/kg) to wild-type mice (C57BL/6J) with HUS did not protect against disease progression. This overall promising, but also contradictory body of evidence, requires further systematic preclinical and clinical investigations to clarify the role of TM in HUS as a potential therapeutic strategy.
Item Metadata
Title |
The Role of the N-Terminal Domain of Thrombomodulin and the Potential of Recombinant Human Thrombomodulin as a Therapeutic Intervention for Shiga Toxin-Induced Hemolytic-Uremic Syndrome
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Creator | |
Contributor | |
Publisher |
Multidisciplinary Digital Publishing Institute
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Date Issued |
2024-09-20
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Description |
Hemolytic-uremic syndrome (HUS) is a rare complication of an infection with Shiga toxin (Stx)-producing Escherichia coli (STEC-HUS), characterized by severe acute kidney injury, thrombocytopenia and microangiopathic hemolytic anemia, and specific therapy is still lacking. Thrombomodulin (TM) is a multi-domain transmembrane endothelial cell protein and its N-terminal domain has been implicated in the pathophysiology of some cases of HUS. Indeed, the administration of recombinant human TM (rhTM) may have efficacy in HUS. We used a Stx-based murine model of HUS to characterize the role of the N-terminal domain of TM. We show that mice lacking that domain (TMLed (−/−)) are more sensitive to Stx, with enhanced HUS progression seen at 4 days and increased mortality at 7 days post-HUS induction. In spite of these changes, renal function was less affected in surviving Stx-challenged TMLed (−/−) mice compared to their wild-type counterparts TMLed (+/+) at 7 days. Contrary to few clinical case reports from Japan, the administration of rhTM (0.06 mg/kg) to wild-type mice (C57BL/6J) with HUS did not protect against disease progression. This overall promising, but also contradictory body of evidence, requires further systematic preclinical and clinical investigations to clarify the role of TM in HUS as a potential therapeutic strategy.
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Subject | |
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Type | |
Language |
eng
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Date Available |
2024-10-11
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Provider |
Vancouver : University of British Columbia Library
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Rights |
CC BY 4.0
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DOI |
10.14288/1.0445555
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URI | |
Affiliation | |
Citation |
Toxins 16 (9): 409 (2024)
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Publisher DOI |
10.3390/toxins16090409
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Peer Review Status |
Reviewed
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Scholarly Level |
Faculty
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DSpace
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Item Media
Item Citations and Data
Rights
CC BY 4.0