Gao Ping, Du Xiaoyi, Liu Lili, Xu Hua, Liu Maochang, Guan Xinlei, Zhang Chengliang
Department of Clinical Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Pharmacol. 2021 Jan 18;11:610102. doi: 10.3389/fphar.2020.610102. eCollection 2020.
Tacrolimus-induced chronic nephrotoxicity (TIN) hinders its long-term use in patients. However, there are no drugs available in the clinic to relieve it at present. Astragaloside IV (AS-IV) is a saponin extract of the which is widely used in the treatment of kidney disease. This study aimed to investigate the effect of AS-IV on TIN and its underlying mechanism. Herein, C57BL/6 mice were treated with tacrolimus and/or AS-IV for 4 weeks, and then the renal function, fibrosis, oxidative stress and p62-Keap1-Nrf2 pathway were evaluated to ascertain the contribution of AS-IV and p62-Keap1-Nrf2 pathway to TIN. Our results demonstrated that AS-IV significantly improved renal function and alleviated tubulointerstitial fibrosis compared with the model group. The expression of fibrosis-related proteins, including TGF-β, Collagen I and α-SMA, were also decreased by AS-IV. Furthermore, AS-IV relieved the inhibition of tacrolimus on antioxidant enzymes. The data in HK-2 cells also proved that AS-IV reduced tacrolimus-induced cell death and oxidative stress. Mechanistically, AS-IV markedly promoted the nuclear translocation of Nrf2 and the renal protective effects of AS-IV were abolished by Nrf2 inhibitor. Further researches showed that phosphorylated p62 was significantly increased after AS-IV pretreatment. Moreover, AS-IV failed to increase nuclear translocation of Nrf2 and subsequent anti-oxidative stress in HK-2 cells transfected with p62 siRNA. Collectively, these findings indicate that AS-IV relieve TIN by enhancing p62 phosphorylation, thereby increasing Nrf2 nuclear translocation, and then alleviating ROS accumulation and renal fibrosis.
他克莫司诱导的慢性肾毒性（TIN）阻碍了其在患者中的长期使用。然而，目前临床上尚无药物可缓解这种情况。黄芪甲苷IV（AS-IV）是黄芪的一种皂苷提取物，广泛用于治疗肾脏疾病。本研究旨在探讨AS-IV对TIN的影响及其潜在机制。在此，将C57BL/6小鼠用他克莫司和/或AS-IV处理4周，然后评估肾功能、纤维化、氧化应激和p62-Keap1-Nrf2通路，以确定AS-IV和p62-Keap1-Nrf2通路对TIN的作用。我们的结果表明，与模型组相比，AS-IV显著改善了肾功能并减轻了肾小管间质纤维化。AS-IV还降低了包括TGF-β、I型胶原蛋白和α-SMA在内的纤维化相关蛋白的表达。此外，AS-IV减轻了他克莫司对抗氧化酶的抑制作用。HK-2细胞中的数据也证明，AS-IV减少了他克莫司诱导的细胞死亡和氧化应激。机制上，AS-IV显著促进了Nrf2的核转位，并且Nrf2抑制剂消除了AS-IV的肾脏保护作用。进一步的研究表明，AS-IV预处理后磷酸化的p62显著增加。此外，在转染了p62 siRNA的HK-2细胞中，AS-IV未能增加Nrf2的核转位及随后的抗氧化应激。总体而言，这些发现表明，AS-IV通过增强p62磷酸化来缓解TIN，从而增加Nrf2核转位，进而减轻ROS积累和肾纤维化。
