Center for Experimental and Molecular Medicine, Amsterdam University Medical Center (UMC), Amsterdam Infection and Immunity Institute, University of Amsterdam, Amsterdam, The Netherlands.
Molecular Cell Biology and Immunology, Amsterdam UMC, Amsterdam Infection and Immunity Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; and.
FASEB J. 2019 Oct;33(10):10966-10972. doi: 10.1096/fj.201900516R. Epub 2019 Jul 9.
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) mice were randomly assigned to vorapaxar (1.75 mg/kg; twice weekly oral gavage) or vehicle treatment, whereas matched wild-type (WT) BTBR (BTBR) mice served as nondiabetic controls. Weight and (nonfasting) 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 mice compared with nondiabetic BTBR controls. Vorapaxar-dependent PAR-1 inhibition reduced but did not normalize blood glucose levels in BTBR 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.
Vorapaxar 依赖性蛋白酶激活受体 (PAR)-1 抑制可减轻 1 型糖尿病实验性糖尿病肾病。由于大多数糖尿病肾病患者患有 2 型糖尿病，因此本研究旨在探讨 PAR-1 抑制是否也可限制 2 型糖尿病实验性糖尿病肾病。因此，将瘦素缺乏的黑棕褐色短毛（BTBR）小鼠随机分为沃拉帕沙（1.75mg/kg；每周两次口服灌胃）或载体处理组，而匹配的野生型（WT）BTBR（BTBR）小鼠作为非糖尿病对照。监测体重和（非空腹）血糖水平长达 18 周，然后评估死后的肾功能和组织学损伤。我们表明，与非糖尿病 BTBR 对照相比，糖尿病 BTBR 小鼠的血糖水平和体重增加。Vorapaxar 依赖性 PAR-1 抑制可降低但不能使 BTBR 小鼠的血糖水平正常化，而体重增加则增强。然而，沃拉帕沙不能保护肾功能，而只能轻微减轻肾脏损伤的组织病理学迹象。总体而言，我们表明 PAR-1 抑制可在 2 型糖尿病实验性糖尿病肾病的进展过程中降低血糖水平，但不能改善肾功能。这与沃拉帕沙在 1 型糖尿病诱导的肾病中的治疗潜力形成对比，突出了依赖疾病的治疗方式的重要性。
