Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease
Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease
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DOI：
10.1152/ajprenal.00595.2019
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发表时间：
2020-05-01
影响因子：
4.2
通讯作者：
Takahashi, Nobuyuki
中科院分区：
文献类型：
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作者：
Mitsui, Shohei;Oe, Yuji;Takahashi, Nobuyuki
蛋白水解酶激活受体(PARs)是凝血酶靶标，在多种疾病中增加炎性细胞因子和趋化因子的表达。在所有的PAR中，以前的报道表明，抑制PAR1或PAR2对糖尿病肾小球损伤具有保护作用。然而，PAR1和PAR2如何协同作用于糖尿病肾病(DKD)的发病机制，以及双重阻断PARS是否对DKD更有效，仍不清楚。为了解决这个问题，内皮型一氧化氮合酶杂合子的雄性I型糖尿病秋田鼠被用作DKD的模型。4月龄小鼠分为4组，分别给予赋形剂、PAR1拮抗剂(E5555，60 mg·kg~(-1)·day(-1))、PAR2拮抗剂(FSLLRY)。3 mg·kg(-1).day(-1))，或E5555+FSLLRY，共4wk。结果表明，E5555+FSLLRY阻断PAR1和PAR2后，与赋形剂治疗组相比，尿白蛋白肌酐比值明显降低。E5555+FSLLRY双重阻断PAR1和PAR2可明显改善肾小球系膜扩张、肾小球巨噬细胞浸润和IV型胶原沉积等组织学损伤。肾脏中炎症和纤维化相关基因的表达也明显减少。在体外，PAR1和PAR2激动剂可增加人内皮细胞巨噬细胞趋化蛋白1或纤溶酶原激活物抑制物1的mRNA表达。PAR1激动剂可被NP-kappa B抑制剂阻断，而PAR2激动剂可被MAPK和/或NF-kappa B抑制剂阻断。这些发现表明，PAR1和PAR2共同参与了DKD的发病过程，同时阻断PAR1和PAR2可能成为治疗DKD患者的一种新的治疗选择。
Protease-activated receptors (PARs) are coagulation protease targets, and they increase expression of inflammatory cytokines and chemokines in various diseases. Of all PARs, previous reports have shown that PAR1 or PAR2 inhibition is protective against diabetic glomerular injury. However, how PAR1 and PAR2 cooperatively contribute to diabetic kidney disease (DKD) pathogenesis and whether dual blockade of PARs is more effective in DKD remain elusive. To address this issue, male type I diabetic Akita mice heterozygous for endothelial nitric oxide synthase were used as a model of DKD. Mice (4 mo old) were divided into four treatment groups and administered vehicle, PAR1 antagonist (E5555, 60 mg.kg(-1).day(-1)), PAR2 antagonist (FSLLRY. 3 mg.kg(-1).day(-1)), or E5555 + FSLLRY for 4 wk. The results showed that the urinary albumin creatinine ratio was significantly reduced when both PAR1 and PAR2 were blocked with E5555 + FSLLRY compared with the vehicle-treated group. Dual blockade of PAR1 and PAR2 by E5555 + FSLLRY additively ameliorated histological injury, including mesangial expansion, glomerular macrophage infiltration, and collagen type IV deposition. Marked reduction of inflammation- and fibrosis-related gene expression in the kidney was also observed. In vitro, PAR1 and PAR2 agonists additively increased mRNA expression of macrophage chemoattractant protein 1 or plasminogen activator inhibitor-1 in human endothelial cells. Changes induced by the PAR1 agonist were blocked by a NP-kappa B inhibitor, whereas those of the PAR2 agonist were blocked by MAPK and/or NF-kappa B inhibitors. These findings suggest that PAR1 and PAR2 additively contribute to DKD pathogenesis and that dual blockade of both could be a novel therapeutic option for treatment of patients with DKD.