成功的顺铂治疗后，多个周期的顺铂会导致肾功能永久性丧失，并伴有严重且终生的慢性肾病（CKD）。最近，研究表明，G 蛋白偶联雌激素受体 (GPER) 的激活可以预防肾脏疾病。本研究旨在测试 G1 化合物（一种 GPER 选择性激动剂）预防顺铂治疗后 CKD 发展的潜力。雄性 C57BL/6 小鼠按照模拟临床暴露的方案接受 2 个周期的 2.5 mg/kg 顺铂（每天注射 1 次，持续 5 天，然后周期之间有 16 天的恢复期）。每天给予 G1（50 或 100 μg/kg），持续 6 周。与顺铂治疗组相比，G1 剂量依赖性地改善肾功能生物标志物（血清肌酐、肌酐清除率和蛋白质排泄）和组织病理学变化。在 G1 处理组中，胶原蛋白 3 的表达呈剂量依赖性下降，这与 Masson 三色染色切片中纤维化的减少是平行的。 G1 给药还增加了总抗氧化能力 (TAC) 和核因子红细胞 2 相关因子 2 (Nrf2)，并降低了丙二醛和促炎细胞因子、肿瘤坏死因子-α 的水平。此外，G1以剂量依赖性方式下调炎症体NLRP3和核因子κB p65（NF-κB p65）的表达。总之，这些数据表明 G1 可能成为顺铂治疗后预防 CKD 的新治疗工具。这些作用可能是通过激活 Nrf2 和抑制 NF-κB/NLRP3 信号传导来介导的。版权所有 © 2024。由 Elsevier B.V. 出版。

Multiple cycles of cisplatin result in a permanent loss of kidney function with severe and life-limited chronic kidney disease (CKD) after successful cisplatin therapy. Recently, studies have showed that the activation of G-protein coupled estrogen receptor (GPER) could protect against kidney disease. This study aimed to test the potential of the G1 compound, a GPER selective agonist, to prevent CKD development after cisplatin therapy. Male C57BL/6 mice were exposed to 2 cycles of 2.5 mg/kg cisplatin in a regimen miming clinical exposure (1 injection daily for 5 days, followed by a 16-day recovery period between cycles). G1 (50 or 100 μg/kg) was administered daily for 6 weeks. G1 dose-dependently improved kidney function biomarkers (serum creatinine, creatinine clearance, and protein excretion) and histopathological changes compared to the cisplatin-treated group. Collagen 3 expression was dose-dependently decreased in G1-treated groups that was parallel to the reduction of fibrosis in Masson's trichrome-stained sections. G1 administration also increased total antioxidant capacity (TAC) and nuclear factor erythroid 2-related factor 2 (Nrf2) and reduced the level of malondialdehyde and the proinflammatory cytokine, tumor necrosis factor-α. In addition, G1 downregulated the expression of inflammasome NLRP3 and nuclear factor kappa B p65 (NF-κB p65) in a dose-dependent manner. In conclusion, these data suggest that G1 could be a new therapeutic tool for CKD prevention post cisplatin therapy. These effects might be mediated through the activation of Nrf2 and the inhibition of NF-κB/NLRP3 signaling.Copyright © 2024. Published by Elsevier B.V.