Research Papers: Pathology:
Vorapaxar treatment reduces mesangial expansion in streptozotocin-induced diabetic nephropathy in mice
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Maaike Waasdorp1, JanWillem Duitman1,2,3, Sandrine Florquin4 and C. Arnold Spek1
1Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands
2Inserm UMR1152, Physiopathologie et Epidémiologie des maladies respiratoires, Medical School Xavier Bichat, Paris, France
3Département Hospitalo-Universitaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
4Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
Maaike Waasdorp, email: [email protected]
Keywords: diabetic nephropathy; vorapaxar; protease-activated receptor-1; mesangial expansion; streptozotocin; Pathology
Received: December 15, 2017 Accepted: March 22, 2018 Published: April 24, 2018
Background: Twenty years after the onset of diabetes, up to 40% of patients develop diabetic nephropathy. Protease-activated receptor-1 (PAR-1) has recently been shown to aggravate the development of experimental diabetic nephropathy. PAR-1 deficient mice develop less albuminuria and glomerular lesions and PAR-1 stimulation induces proliferation and fibronectin production in mesangial cells in vitro. Vorapaxar is a clinically available PAR-1 inhibitor which is currently used for secondary prevention of ischemic events.
Objectives: The aim of this study was to investigate in a preclinical setting whether vorapaxar treatment may be a novel strategy to reduce diabetes-induced kidney damage.
Results: While control treated diabetic mice developed significant albuminuria, mesangial expansion and glomerular fibronectin deposition, diabetic mice on vorapaxar treatment did not show any signs of kidney damage despite having similar levels of hyperglycemia.
Conclusions: These data show that PAR-1 inhibition by vorapaxar prevents the development of diabetic nephropathy in this preclinical animal model for type I diabetes and pinpoint PAR-1 as a novel therapeutic target to pursue in the setting of diabetic nephropathy.
Materials and Methods: 22 C57Bl/6 mice were made diabetic using multiple low-dose streptozotocin injections (50 mg/kg) and 22 littermates served as non-diabetic controls. Four weeks after the induction of diabetes, 11 mice of each group were assigned to control or vorapaxar treatment. Mice were sacrificed after 20 weeks of treatment and kidney damage was evaluated.
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