Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Pharmacol Res. 2023 Mar;189:106680. doi: 10.1016/j.phrs.2023.106680. Epub 2023 Feb 4.
Acute kidney injury (AKI) is a common clinical complication. Cisplatin (Cis) is an effective chemotherapeutic drug; however, its acute nephrotoxicity often limits its application. The role of liraglutide (Lir), an agonist of the glucagon-like peptide-1 receptor (GLP-1R), has recently attracted increasing attention beyond glycemic regulation. This study showed that Lir significantly ameliorated Cis-induced kidney dysfunction and renal damage. However, this renoprotective effect was partially abolished in GLP-1R knockout (GLP-1R) mice. Furthermore, we synthesized Lir metabolites, GLP-1 (9-37) and GLP-1 (28-37), and found that they also exerted reno-protective effects that were not impaired in GLP-1R mice. We also demonstrated that Lir and its metabolites reduced cisplatin-induced apoptosis in human renal tubular epithelial cells (HK-2). After silencing GLP-1R expression in HK-2 cells with small interfering ribose nucleic acid (siRNA), the protective effect of Lir on HK-2 cells was inhibited, while the protective effects of GLP-1 (9-37) and GLP-1 (28-37) were not affected. Additionally, we demonstrated that Lir and its metabolites inhibited Cis-induced high-mobility group box 1 (HMGB1) nuclear-cytoplasmic translocation and release, and reduced inflammatory cytokines and HMGB1 receptor expression. The exogenous use of recombinant HMGB1 (rHMGB1) dramatically weakened the protective effects of Lir and its metabolites. In conclusion, our study shows that Lir significantly attenuated Cis-induced AKI through GLP-1R dependent and independent pathways, mediated by inhibiting nuclear-cytoplasmic translocation and release of HMGB1. Lir and its metabolites may be effective drugs for treating cisplatin-induced nephrotoxicity.
急性肾损伤（AKI）是一种常见的临床并发症。顺铂（Cis）是一种有效的化疗药物；然而，其急性肾毒性常限制其应用。利拉鲁肽（Lir），一种胰高血糖素样肽-1 受体（GLP-1R）激动剂的作用，除了血糖调节外，最近引起了越来越多的关注。本研究表明，Lir 显著改善 Cis 诱导的肾功能障碍和肾损伤。然而，这种肾保护作用在 GLP-1R 敲除（GLP-1R）小鼠中部分被消除。此外，我们合成了 Lir 的代谢产物，GLP-1（9-37）和 GLP-1（28-37），并发现它们也具有肾保护作用，在 GLP-1R 小鼠中不受损害。我们还证明 Lir 及其代谢产物可减少顺铂诱导的人肾小管上皮细胞（HK-2）凋亡。用小干扰核糖核酸（siRNA）沉默 HK-2 细胞中的 GLP-1R 表达后，Lir 对 HK-2 细胞的保护作用被抑制，而 GLP-1（9-37）和 GLP-1（28-37）的保护作用不受影响。此外，我们证明 Lir 及其代谢产物可抑制 Cis 诱导的高迁移率族蛋白 B1（HMGB1）核-胞质易位和释放，并减少炎症细胞因子和 HMGB1 受体表达。外源性使用重组 HMGB1（rHMGB1）显著削弱了 Lir 及其代谢产物的保护作用。总之，本研究表明，Lir 通过 GLP-1R 依赖和非依赖途径显著减轻 Cis 诱导的 AKI，其机制可能是通过抑制 HMGB1 的核-胞质易位和释放。Lir 和其代谢产物可能是治疗顺铂诱导的肾毒性的有效药物。
