Protease-Activated Receptor 1 Contributes to Microcirculation Failure and Tubular Damage in Renal Ischemia-Reperfusion Injury in Mice.
Protease-Activated Receptor 1 Contributes to Microcirculation Failure and Tubular Damage in Renal Ischemia-Reperfusion Injury in Mice.
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DOI：
10.1155/2021/6665714
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发表时间：
2021
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Guan Y;Nakano D;Li L;Zheng H;Nishiyama A;Tian Y;Zhang L
缺血再灌注（IR）诱导的肾损伤在肾移植和机器人辅助肾部分切除术中难以避免。肾IR损伤的特征在于肾小管损伤、微循环衰竭和炎症，这些共同加重肾损伤;然而，对于这些病症没有特异性治疗。蛋白酶激活受体-1（PAR-1）及其配体凝血酶参与凝血，并与上皮细胞损伤有关。在这里，我们假设PAR-1夸大了肾IR诱导的肾小管细胞损伤和微循环衰竭，Q94对PAR-1的药理学抑制可以防止这些损伤。肾热IR可增加肾小管PAR-1的表达。Q94可减轻IR引起的肾脏病理改变。通过组织病理学中的充血分析的微循环衰竭和通过活体多光子显微镜检查的血细胞流动被Q94治疗抑制。Q94还显著增加肾小管细胞增殖，尽管肾损伤较低。凝血酶抑制细胞增殖和诱导细胞凋亡的小管，这些影响被阻止Q94治疗。总之，PAR-1与肾IR损伤相关。抑制PAR-1可能通过改善肾微循环和肾小管细胞存活/增殖来改善损伤。
Ischemia-reperfusion- (IR-) induced kidney injury is difficult to avoid during renal transplantation and robot-assisted partial nephrectomy. Renal IR injury is characterized by tubular damage, microcirculation failure, and inflammation, which coordinately augment renal injury; however, no specific treatment is available for these conditions. Protease-activated receptor-1 (PAR-1) and its ligand, thrombin, are involved in coagulation and were shown to be associated with epithelial cell injury. Here, we hypothesized that PAR-1 exaggerated renal IR-induced tubular cell damage and microcirculation failure and that pharmacological inhibition of PAR-1 by Q94 could prevent these injuries. Renal warm IR increased the expression of PAR-1 in the renal tubules. Q94 attenuated renal IR-induced changes and histopathological damage. Microcirculation failure analyzed by congestion in the histopathology and blood cell flow examined by intravital multiphoton microscopy were suppressed by Q94 treatment. Q94 also dramatically increased tubular cell proliferation despite the lower renal damage. Thrombin suppressed cell proliferation and induced apoptosis in the tubules; these effects were prevented by Q94 treatment. Taken together, PAR-1 was associated with renal IR injury. Inhibition of PAR-1 ameliorated injury possibly by improving renal microcirculation and tubular cell survival/proliferation.
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