Protease-activated receptor-1 deficiency protects against streptozotocin-induced diabetic nephropathy in mice

Endogenously administered activated protein C ameliorates diabetic nephropathy (DN) in a protease-activated receptor-1 (PAR-1)-dependent manner, suggesting that PAR-1 activation limits the progression of DN. Activation of PAR-1 in fibroblast-like cells, however, induces proliferation and extracellul...

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Veröffentlicht in:Scientific reports Jg. 6; H. 1; S. 33030
Hauptverfasser: Waasdorp, Maaike, Duitman, JanWillem, Florquin, Sandrine, Spek, C. Arnold
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 13.09.2016
Nature Publishing Group
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Activated protein C
Animals
Atrophy
Cell Proliferation
Collagen (type IV)
Cystatin C
Diabetes
Diabetes mellitus
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Experimental - pathology
Diabetes Mellitus, Experimental - prevention & control
Diabetic Nephropathies - genetics
Diabetic Nephropathies - metabolism
Diabetic Nephropathies - pathology
Diabetic Nephropathies - prevention & control
Diabetic nephropathy
Epithelial cells
Extracellular matrix
Fibronectin
Glucose
Humanities and Social Sciences
Kidney Tubules - injuries
Kidney Tubules - metabolism
Kidney Tubules - pathology
Kidneys
Mesangial cells
Mesangial Cells - metabolism
Mesangial Cells - pathology
Mice
Mice, Knockout
multidisciplinary
Nephropathy
Protein C
Proteinase
Proteinase-activated receptor 1
Proteinuria
Receptor, PAR-1 - deficiency
Rodents
Science
Streptozocin
ISSN:2045-2322, 2045-2322
Online-Zugang:Volltext
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Zusammenfassung:Endogenously administered activated protein C ameliorates diabetic nephropathy (DN) in a protease-activated receptor-1 (PAR-1)-dependent manner, suggesting that PAR-1 activation limits the progression of DN. Activation of PAR-1 in fibroblast-like cells, however, induces proliferation and extracellular matrix production, thereby driving fibrotic disease. Considering the key role of mesangial proliferation and extracellular matrix production during DN, PAR-1 may in fact potentiate diabetes-induced kidney injury. To determine the net effect of PAR-1 in DN, streptozotocin-induced DN was studied in wild type and PAR-1 deficient mice. Subsequent mechanistic insight was obtained by assessing profibrotic responses of mesangial and tubular epithelial cells in vitro , following PAR-1 stimulation and inhibition. Despite having similar glucose levels, PAR-1 deficient mice developed less kidney damage after induction of diabetes, as evidenced by diminished proteinuria, plasma cystatin C levels, expansion of the mesangial area, and tubular atrophy. In vitro , PAR-1 signaling in mesangial cells led to increased proliferation and expression of matrix proteins fibronectin and collagen IV. Conversely, a reduction in both proliferation and fibronectin deposition was observed in diabetic PAR-1 deficient mice. Overall, we show that PAR-1 plays an important role in the development of DN and PAR-1 might therefore be an attractive therapeutic target to pursue in DN.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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Present address: Université Paris Diderot, Sorbonne Paris Cité, Département Hospitalo-universitaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France.
These authors contributed equally to this work.
Present address: Inserm UMR1152, Physiopathologie et Epidémiologie des maladies respiratoires, Medical School Xavier Bichat, Paris, France.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep33030