Department of Nephrology, The Second Affiliated Hospital of Shenzhen University, Shenzhen 518000, Guangdong, China.
Department of Nephrology, The People's Hospital of Baoan Shenzhen, The Second School of Clinical Medicine, Southern Medical University, Shenzhen 518000, Guangdong, China.
Mediators Inflamm. 2023 Jul 13;2023:5007488. doi: 10.1155/2023/5007488. eCollection 2023.
Interstitial inflammation is an important mechanism of pathological damage in renal injury caused by hyperuricemia. Protease-activated receptor-2 (PAR2) is a class of targets that act upstream of the PI3K/AKT/NF-B pathway and is involved in various inflammatory diseases. We induced a hyperuricemia model in rats by adenine and ethambutol gavage in an experiment. We demonstrated that PAR2 and PI3K/AKT/NF-B pathway expression were significantly upregulated in renal tissues, with massive inflammatory cell infiltration in the renal interstitium and renal tissue injury. Treating hyperuricemic rats with AZ3451, a selective metabotropic antagonist of PAR2, we demonstrated that PAR2 antagonism inhibited the PI3K/AKT/NF-B pathway and attenuated tubular dilation and tubulointerstitial inflammatory cell infiltration. The phospholipid metabolism profiles provided a perfect separation between the normal and hyperuricemic rats. In addition, we also found that AZ3451 can affect phospholipid metabolism. Our work suggests that PAR2 may mediate hyperuricemia-mediated renal injury by activating the PI3K/AKT/NF-B pathway. The PAR2 antagonist AZ3451 may be a promising therapeutic strategy for hyperuricemia-induced inflammatory responses.
间质炎症是高尿酸血症引起肾损伤病理损伤的重要机制。蛋白酶激活受体-2（PAR2）是作用于 PI3K/AKT/NF-B 途径上游的一类靶点，参与多种炎症性疾病。我们通过腺嘌呤和乙胺丁醇灌胃在实验中诱导大鼠高尿酸血症模型。结果表明，肾组织中 PAR2 和 PI3K/AKT/NF-B 途径的表达明显上调，肾间质和肾组织中大量炎症细胞浸润。用 PAR2 的选择性代谢型拮抗剂 AZ3451 处理高尿酸血症大鼠，结果表明 PAR2 拮抗作用抑制了 PI3K/AKT/NF-B 途径，减轻了肾小管扩张和肾小管间质炎症细胞浸润。磷脂代谢谱在正常和高尿酸血症大鼠之间提供了完美的分离。此外，我们还发现 AZ3451 可以影响磷脂代谢。我们的工作表明，PAR2 可能通过激活 PI3K/AKT/NF-B 途径介导高尿酸血症引起的肾损伤。PAR2 拮抗剂 AZ3451 可能是高尿酸血症诱导的炎症反应的一种有前途的治疗策略。
