Vorapaxar treatment reduces mesangial expansion in streptozotocin-induced diabetic nephropathy in mice

Maaike Waasdorp*, Jan Willem Duitman, Sandrine Florquin, C. Arnold Spek

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 nondiabetic 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.

Original languageEnglish
Pages (from-to)21655-21662
Number of pages8
JournalOncotarget
Volume9
Issue number31
DOIs
Publication statusPublished - 24 Apr 2018
Externally publishedYes

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