Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Department of Pharmacology, Kagawa University, Kagawa, Japan.
Biomed Res Int. 2021 Feb 23;2021:6665714. doi: 10.1155/2021/6665714. eCollection 2021.
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.
缺血再灌注（IR）引起的肾损伤在肾移植和机器人辅助部分肾切除术过程中难以避免。肾 IR 损伤的特征是肾小管损伤、微循环衰竭和炎症，这些共同加重了肾损伤；然而，目前尚无针对这些情况的特定治疗方法。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 可加重肾 IR 诱导的肾小管细胞损伤和微循环衰竭，而通过 Q94 抑制 PAR-1 可预防这些损伤。肾温热 IR 增加了肾小管中 PAR-1 的表达。Q94 减轻了肾 IR 诱导的变化和组织病理学损伤。组织病理学中通过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被 Q94 治疗抑制。尽管肾损伤较低，Q94 仍显著增加了管状细胞的增殖。凝血酶抑制了肾小管中的细胞增殖并诱导细胞凋亡；这些作用通过 Q94 治疗得到预防。综上所述，PAR-1 与肾 IR 损伤有关。PAR-1 抑制可通过改善肾微循环和肾小管细胞存活/增殖来减轻损伤。
