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Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy

Whereas it is generally perceived to be harmful, enhanced coagulation activation can also convey salutary effects. The high prevalence of the prothrombotic factor V Leiden (FVL) mutation in whites has been attributed to a positive selection pressure (eg, resulting from reduced blood loss or improved...

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Main Authors: Wang, Hongjie (Author) , Madhusudhan, Thati (Author) , He, Tao (Author) , Hummel, Björn Alexander (Author) , Schmidt, Simone (Author) , Vinnikov, Ilya A. (Author) , Shahzad Hussain, Khurrum (Author) , Kashif, Muhammed (Author) , Müller-Krebs, Sandra (Author) , Schwenger, Vedat (Author) , Bierhaus, Angelika (Author) , Rudofsky, Gottfried (Author) , Nawroth, Peter Paul (Author) , Isermann, Berend (Author)
Format: Article (Journal)
Language:English
Published: March 9, 2011
In: Blood
Year: 2011, Volume: 117, Issue: 19, Pages: 5231-5242
ISSN:1528-0020
DOI:10.1182/blood-2010-10-314773
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood-2010-10-314773
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Author Notes:Hongjie Wang, Thati Madhusudhan, Tao He, Björn Hummel, Simone Schmidt, Ilya A. Vinnikov, Khurrum Shahzad, Muhammed Kashif, Sandra Muller-Krebs, Vedat Schwenger, Angelika Bierhaus, Gottfried Rudofsky, Peter P. Nawroth, and Berend Isermann
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Summary:Whereas it is generally perceived to be harmful, enhanced coagulation activation can also convey salutary effects. The high prevalence of the prothrombotic factor V Leiden (FVL) mutation in whites has been attributed to a positive selection pressure (eg, resulting from reduced blood loss or improved survival in sepsis). The consequences of enhanced coagulation activation, as observed in FVL carriers, on microvascular diabetic complications remain unknown. We therefore investigated the role of FVL in diabetic nephropathy. In heterozygous or homozygous diabetic FVL mice, albuminuria and indices of diabetic nephropathy were reduced compared with diabetic wild-type mice. This was associated with reduced glomerular apoptosis and preservation of podocytes in diabetic FVL-positive mice. In vitro, low-dose thrombin (50pM) prevented, whereas high-dose thrombin (20nM) aggravated, glucose-induced apoptosis in podocytes. In diabetic patients, the FVL mutation, but not the plasminogen activator inhibitor-1 4G/5G polymorphism, is associated with reduced albuminuria, which is consistent with a nephroprotective role of low but sustained thrombin generation. Consistently, anticoagulation of diabetic FVL-positive mice with hirudin abolished the nephroprotective effect. These results identify a nephroprotective function of low but sustained thrombin levels in FVL carriers, supporting a dual, context-dependent function of thrombin in chronic diseases.
Item Description:Gesehen am 15.11.2022
Physical Description:Online Resource
ISSN:1528-0020
DOI:10.1182/blood-2010-10-314773

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