UCD School of Biomolecular and Biomedical Research, UCD Conway Institute, University College Dublin, Dublin 4, Ireland.
Toxicol Sci. 2012 Mar;126(1):101-13. doi: 10.1093/toxsci/kfr330. Epub 2011 Dec 6.
Cyclosporine A (CsA) is a potent immunosuppressant used to prevent organ transplant rejection and in the treatment of autoimmune diseases. However, chronic CsA nephropathy is the major limiting factor to its widespread use. The exact mechanisms of CsA-induced renal damage remain to be fully elucidated. The objective of the current research was to examine whether CsA treatment induced any glomerular mesangial cell alterations. In this research goal, human mesangial cells (HMCs) were treated with CsA for various time points. CsA caused an increase in the production of reactive oxygen species (ROS). Microarray analysis of mesangial cells treated with CsA also indicated 282 dysregulated genes. Bioinformatic analysis of these 282 genes indicated enriched apoptotic oxidative stress, mitogen-activated protein kinase (MAPK), and transforming growth factor-β signaling in response to CsA treatment. The focus of this study was directed on oxidative stress and MAPK signaling as potential novel mechanisms of CsA nephrotoxicity. One key contributor to oxidative stress, thioredoxin interacting protein, was significantly upregulated following CsA treatment. Inhibition of the MAPK pathway resulted in attenuation of the CsA-induced mesangial cell alterations. These findings suggest a major role for ROS, oxidative stress, and MAPK signaling in promoting CsA-induced glomerular dysfunction and subsequent nephrotoxicity.
环孢素 A（CsA）是一种强效免疫抑制剂，用于预防器官移植排斥反应和治疗自身免疫性疾病。然而，慢性 CsA 肾病是其广泛应用的主要限制因素。CsA 诱导肾损伤的确切机制仍有待充分阐明。本研究旨在探讨 CsA 治疗是否会引起肾小球系膜细胞的改变。在本研究目标中，用 CsA 处理人肾小球系膜细胞（HMC）不同时间点。CsA 导致活性氧（ROS）的产生增加。CsA 处理的系膜细胞的微阵列分析也表明有 282 个基因失调。对这 282 个基因的生物信息学分析表明，CsA 处理后凋亡氧化应激、丝裂原活化蛋白激酶（MAPK）和转化生长因子-β信号通路富集。本研究的重点是氧化应激和 MAPK 信号作为 CsA 肾毒性的潜在新机制。硫氧还蛋白相互作用蛋白是氧化应激的一个关键贡献者，在 CsA 处理后显著上调。MAPK 通路的抑制导致 CsA 诱导的系膜细胞改变减弱。这些发现表明 ROS、氧化应激和 MAPK 信号在促进 CsA 诱导的肾小球功能障碍和随后的肾毒性中起主要作用。
