Vorapaxar treatment reduces mesangial expansion in streptozotocin-induced diabetic nephropathy in mice.
Vorapaxar treatment reduces mesangial expansion in streptozotocin-induced diabetic nephropathy in mice.
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DOI：
10.18632/oncotarget.25069
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发表时间：
2018-04-24
期刊：
影响因子：
--
通讯作者：
Spek CA
中科院分区：
文献类型：
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作者：
Waasdorp M;Duitman J;Florquin S;Spek CA
糖尿病发病20年后，高达40%的患者发展为糖尿病肾病。蛋白酶激活受体 1 (PAR-1) 最近被证明会加剧实验性糖尿病肾病的发展。 PAR-1 缺陷小鼠出现较少的蛋白尿和肾小球病变，并且 PAR-1 刺激可在体外诱导系膜细胞增殖和纤连蛋白产生。 Vorapaxar是一种临床可用的PAR-1抑制剂，目前用于缺血事件的二级预防。本研究的目的是在临床前环境中调查沃拉帕沙治疗是否可能是减少糖尿病引起的肾脏损害的新策略。对照治疗的糖尿病小鼠出现显着的蛋白尿、系膜扩张和肾小球纤连蛋白沉积，而接受沃拉帕沙治疗的糖尿病小鼠尽管具有相似的高血糖水平，但没有表现出任何肾脏损伤的迹象。这些数据表明，vorapaxar 抑制 PAR-1 可预防 I 型糖尿病临床前动物模型中糖尿病肾病的发展，并将 PAR-1 确定为糖尿病肾病治疗的新治疗靶点。通过多次低剂量链脲佐菌素注射（50 mg/kg）使 22 只 C57Bl/6 小鼠患上糖尿病，22 只同窝小鼠作为非糖尿病对照。诱导糖尿病 4 周后，每组 11 只小鼠被分配接受对照或沃拉帕沙治疗。治疗20周后处死小鼠并评估肾损伤。
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. 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. 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. 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. 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.