Pharmacological PAR‐1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy

Vorapaxar‐dependent protease‐activated receptor (PAR)‐1 inhibition diminishes diabetic nephropathy in experimental type 1 diabetes. As most patients with diabetic nephropathy suffer from type 2 diabetes, the aim of this study was to investigate whether PAR‐1 inhibition also limits diabetic nephropathy in experimental type 2 diabetes. Consequently, leptin‐deficient black and tan brachyuric (BTBR ob/ob ) mice were randomly assigned to vorapaxar (1.75 mg/kg; twice weekly via oral gavage) or vehicle treatment, whereas matched wild‐type (WT) BTBR (BTBR WT ) mice served as nondiabetic controls. Weight and (non‐fasting) blood glucose levels were monitored for up to 18 wk, after which kidney function and histologic damage was evaluated postmortem. We show that blood glucose levels and body weight increased in diabetic BTBR ob/ob mice compared with nondiabetic BTBR WT controls. Vorapaxar‐dependent PAR‐1 inhibition reduced but did not normalize blood glucose levels in BTBR ob/ob mice, whereas it potentiated the increase in body weight. Vorapaxar did not, however, preserve kidney function, whereas it only minimally reduced histopathological signs of kidney injury. Overall, we thus show that PAR‐1 inhibition reduces blood glucose levels during the progression of diabetic nephropathy in experimental type 2 diabetes but does not improve renal function. This is in contrast to the therapeutic potential of vorapaxar in type 1 diabetes‐induced nephropathy, highlighting the importance of disease‐dependent treatment modalities.—Waasdorp, M., Florquin, S., Duitman, J., Spek, C. A. Pharmacological PAR‐1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy. FASEB J. 33, 10966–10972 (2019). www.fasebj.org