Key Laboratory of Shannxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Clinical Research Center of Shannxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
J Biochem Mol Toxicol. 2020 May;34(5):e22467. doi: 10.1002/jbt.22467. Epub 2020 Feb 10.
Oxidative stress induced by long-term cyclosporine A (CsA) administration is a major cause of chronic nephrotoxicity, which is characterized by tubular atrophy, tubular cell apoptosis, and interstitial fibrosis in the progression of organ transplantation. Although hydrogen-rich water (HRW) has been used to prevent various oxidative stress-related diseases, its underlying mechanisms remain unclear. This study investigated the effects of HRW on CsA-induced nephrotoxicity and its potential mechanisms. After administration of CsA (25 mg/kg/day), rats were treated with or without HRW (12 mL/kg) for 4 weeks. Renal function and vascular activity were investigated. Histological changes in kidney tissues were analyzed using Masson's trichrome and terminal deoxynucleotidyl transferase dUTP nick-end labeling stains. Oxidative stress markers and the activation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway were also measured. We found that CsA increased the levels of reactive oxygen species (ROS) and malonaldehyde (MDA), but it reduced glutathione (GSH) and superoxide dismutase (SOD) levels. Such alterations induced vascular dysfunction, tubular atrophy, interstitial fibrosis, and tubular apoptosis. This was evident secondary to an increase in urinary protein, serum creatinine, and blood urea nitrogen, ultimately leading to renal dysfunction. Conversely, HRW decreased levels of ROS and MDA while increasing the activity of GSH and SOD. This was accompanied by an improvement in vascular and renal function. Moreover, HRW significantly decreased the level of Keap1 and increased the expression of Nrf2, NADPH dehydrogenase quinone 1, and heme oxygenase 1. In conclusion, HRW restored the balance of redox status, suppressed oxidative stress damage, and improved kidney function induced by CsA via activation of the Keap1/Nrf2 signaling pathway.
长期使用环孢素 A（CsA）会导致氧化应激，这是慢性肾毒性的主要原因，它的特征是在器官移植过程中发生肾小管萎缩、肾小管细胞凋亡和间质纤维化。尽管富氢水（HRW）已被用于预防各种与氧化应激相关的疾病，但它的潜在机制仍不清楚。本研究探讨了 HRW 对 CsA 诱导的肾毒性及其潜在机制的影响。在给予 CsA（25mg/kg/天）后，大鼠用或不用 HRW（12mL/kg）治疗 4 周。研究了肾功能和血管活性。用 Masson 三色和末端脱氧核苷酸转移酶 dUTP 末端标记染色分析肾脏组织的组织学变化。还测量了氧化应激标志物和 Kelch 样 ECH 相关蛋白 1（Keap1）/核因子红细胞 2 相关因子 2（Nrf2）信号通路的激活。我们发现，CsA 增加了活性氧（ROS）和丙二醛（MDA）的水平，但降低了谷胱甘肽（GSH）和超氧化物歧化酶（SOD）的水平。这种改变诱导了血管功能障碍、肾小管萎缩、间质纤维化和肾小管凋亡。这是由于尿蛋白、血清肌酐和血尿素氮增加，导致肾功能不全。相反，HRW 降低了 ROS 和 MDA 的水平，同时增加了 GSH 和 SOD 的活性。这伴随着血管和肾功能的改善。此外，HRW 显著降低了 Keap1 的水平，增加了 Nrf2、NADPH 脱氢酶醌 1 和血红素加氧酶 1 的表达。总之，HRW 通过激活 Keap1/Nrf2 信号通路，恢复了氧化还原状态的平衡，抑制了 CsA 诱导的氧化应激损伤，改善了肾功能。
