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Studies of ADAMTS13 expression and activity in the kidney

Tati, Ramesh LU (2013) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2013:18.
Abstract
Von Willebrand factor (VWF) is an abundant plasma glycoprotein involved in platelet adhesion and aggregation at sites of vascular injury. ADAMTS13 is the sole physiological VWF-cleaving protease, thus regulating the size of thrombus growth. Dysfunctional ADAMTS13 leads to thrombotic thrombocytopenic purpura (TTP), which is either due to mutations (congenital TTP) or auto-antibodies (acquired TTP). The histopathological lesion is termed thrombotic microangiopathy and characterized by disseminated hyaline thrombi in the microvasculature of various organs including the kidney. The present study aimed to investigate ADAMTS13 expression and activity in the kidney.

Cultured renal tubular epithelial cells were shown to express... (More)
Von Willebrand factor (VWF) is an abundant plasma glycoprotein involved in platelet adhesion and aggregation at sites of vascular injury. ADAMTS13 is the sole physiological VWF-cleaving protease, thus regulating the size of thrombus growth. Dysfunctional ADAMTS13 leads to thrombotic thrombocytopenic purpura (TTP), which is either due to mutations (congenital TTP) or auto-antibodies (acquired TTP). The histopathological lesion is termed thrombotic microangiopathy and characterized by disseminated hyaline thrombi in the microvasculature of various organs including the kidney. The present study aimed to investigate ADAMTS13 expression and activity in the kidney.

Cultured renal tubular epithelial cells were shown to express biologically active ADAMTS13. Renal tissues from patients with tubulopathy exhibited an altered ADAMTS13 expression pattern in comparison to controls. ADAMTS13 was detected in urine from patients with tubulopathy suggesting local synthesis. Cultured glomerular endothelial cells were also shown to express biologically active ADAMTS13. ADAMTS13-deficiency in mice led to glomerular capillary vessel wall thickening and platelet deposition as demonstrated by electron microscopy. ADAMTS13 was also detected in the glomerular basement membrane (GBM), however its role in VWF-cleavage in the GBM appeared to be minimal, whereas serine protease activity accounted for most of the cleavage. ADAMTS13 deficiency led to complement deposition in kidney from TTP patients and from ADAMTS13-deficient mice. Plasma from TTP patients contained high levels of complement (C3 and C9)-coated endothelial microparticles. Experiments using plasma/serum samples from the patients with added normal platelets perfused over glomerular endothelial cells demonstrated C3 deposition on VWF-platelet strings and on the endothelial cells. Perfusion of patient plasma induced more release of C3- and C9-coated endothelial microparticles than control plasma.

The experimental work in this thesis provides evidence for ADAMTS13 in renal tissue including tubular cells, GBM and glomerular endothelial cells. Local production of the protease may contribute to protection of glomerular vessels from injury, in addition to circulatory ADAMTS13. ADAMTS13 deficiency promoted complement deposition which may further aggravate the vascular damage. (Less)
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author
supervisor
opponent
  • Noris, Marina, Head of The Laboratory of Immunology and Genetics of Transplantation and Rare Diseases
organization
publishing date
type
Thesis
publication status
published
subject
keywords
ADAMTS13, von WIllebrand factor, thrombotic thrombocytopenic purpura
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2013:18
pages
169 pages
publisher
Paediatrics, Faculty of Medicine, Lund University
defense location
Belfragesalen, Biomedicinskt Centrum (BMC), D15, Klinikgatan 32, Lund.
defense date
2013-03-07 09:00
ISSN
1652-8220
ISBN
978-91-87189-87-6
language
English
LU publication?
yes
id
3da5df45-67c5-47ce-8505-1a0247180ea0 (old id 3469750)
date added to LUP
2013-02-21 08:38:09
date last changed
2018-11-21 20:28:28
@phdthesis{3da5df45-67c5-47ce-8505-1a0247180ea0,
  abstract     = {Von Willebrand factor (VWF) is an abundant plasma glycoprotein involved in platelet adhesion and aggregation at sites of vascular injury. ADAMTS13 is the sole physiological VWF-cleaving protease, thus regulating the size of thrombus growth. Dysfunctional ADAMTS13 leads to thrombotic thrombocytopenic purpura (TTP), which is either due to mutations (congenital TTP) or auto-antibodies (acquired TTP). The histopathological lesion is termed thrombotic microangiopathy and characterized by disseminated hyaline thrombi in the microvasculature of various organs including the kidney. The present study aimed to investigate ADAMTS13 expression and activity in the kidney.<br/><br>
Cultured renal tubular epithelial cells were shown to express biologically active ADAMTS13. Renal tissues from patients with tubulopathy exhibited an altered ADAMTS13 expression pattern in comparison to controls. ADAMTS13 was detected in urine from patients with tubulopathy suggesting local synthesis. Cultured glomerular endothelial cells were also shown to express biologically active ADAMTS13. ADAMTS13-deficiency in mice led to glomerular capillary vessel wall thickening and platelet deposition as demonstrated by electron microscopy. ADAMTS13 was also detected in the glomerular basement membrane (GBM), however its role in VWF-cleavage in the GBM appeared to be minimal, whereas serine protease activity accounted for most of the cleavage. ADAMTS13 deficiency led to complement deposition in kidney from TTP patients and from ADAMTS13-deficient mice. Plasma from TTP patients contained high levels of complement (C3 and C9)-coated endothelial microparticles. Experiments using plasma/serum samples from the patients with added normal platelets perfused over glomerular endothelial cells demonstrated C3 deposition on VWF-platelet strings and on the endothelial cells. Perfusion of patient plasma induced more release of C3- and C9-coated endothelial microparticles than control plasma. <br/><br>
The experimental work in this thesis provides evidence for ADAMTS13 in renal tissue including tubular cells, GBM and glomerular endothelial cells. Local production of the protease may contribute to protection of glomerular vessels from injury, in addition to circulatory ADAMTS13. ADAMTS13 deficiency promoted complement deposition which may further aggravate the vascular damage.},
  author       = {Tati, Ramesh},
  isbn         = {978-91-87189-87-6},
  issn         = {1652-8220},
  keyword      = {ADAMTS13,von WIllebrand factor,thrombotic thrombocytopenic purpura},
  language     = {eng},
  pages        = {169},
  publisher    = {Paediatrics, Faculty of Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Studies of ADAMTS13 expression and activity in the kidney},
  volume       = {2013:18},
  year         = {2013},
}