Waasdorp Maaike, Duitman JanWillem, Florquin Sandrine, Spek C Arnold
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Inserm UMR1152, Physiopathologie et Epidémiologie des maladies respiratoires, Medical School Xavier Bichat, Paris, France.
Oncotarget. 2018 Apr 24;9(31):21655-21662. doi: 10.18632/oncotarget.25069.
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 . 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.
糖尿病发病20年后，高达40%的患者会发展为糖尿病肾病。蛋白酶激活受体-1（PAR-1）最近被证明会加重实验性糖尿病肾病的发展。PAR-1基因缺陷小鼠的蛋白尿和肾小球病变较少，而PAR-1刺激可诱导系膜细胞增殖和纤连蛋白生成。沃拉帕沙是一种临床可用的PAR-1抑制剂，目前用于缺血性事件的二级预防。
本研究旨在通过临床前研究探讨沃拉帕沙治疗是否可能是减少糖尿病所致肾损伤的新策略。
对照治疗的糖尿病小鼠出现了显著的蛋白尿、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血糖水平相似，但未表现出任何肾损伤迹象。
这些数据表明，在该I型糖尿病临床前动物模型中，沃拉帕沙抑制PAR-1可预防糖尿病肾病的发展，并确定PAR-1是糖尿病肾病治疗中一个新的治疗靶点。
通过多次低剂量链脲佐菌素注射（50mg/kg）使22只C57Bl/6小鼠患糖尿病，22只同窝小鼠作为非糖尿病对照。糖尿病诱导4周后，每组11只小鼠分别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情况。
