College of Life Science, Yangtze University, Jingzhou, 434025, China; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic; Jingchu Food Research and Development Center, Yangtze University, Jingzhou, 434025, China.
National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, 430070, China.
Food Chem Toxicol. 2018 Aug;118:889-907. doi: 10.1016/j.fct.2018.06.054. Epub 2018 Jun 28.
Cyclosporine A (CsA) is a widely used immunosuppressive agent that greatly reduces the rates of kidney-, heart-, and liver-transplant rejection. However, CsA nephrotoxicity is a serious side effect that limits the clinical use of CsA. While the mechanisms underlying CsA nephrotoxicity are still not fully understood, increasing lines of evidence suggest that oxidative stress plays an important role in this phenomenon. Specifically, CsA induces endoplasmic reticulum stress and increases mitochondrial reactive oxygen species production: this modifies the redox balance, which causes lipid peroxidation and thereby induces nephrotoxicity. Recent studies on the pathogenesis of CsA nephrotoxicity suggest that CsA-induced autophagy can alleviate the deleterious effects of CsA-induced endoplasmic reticulum stress, thereby preventing nephrotoxicant-induced renal injury. A variety of signaling pathways participate in the pathogenesis of CsA nephrotoxicity. Specifically, the p38, ERK, and JNK MAPK subfamilies are all involved in CsA nephrotoxicity, while NF-κB is a target molecule of CsA. Moreover, the fibrogenic cytokine TGF-β1 contributes to CsA-induced renal fibrosis, while Nrf2 modulates CsA-induced cellular oxidative stress. In addition, CsA generally inhibits nitric oxide synthesis and impairs endothelium-dependent relaxation in the renal artery. However, some reports also suggest that nitric oxide synthesis is enhanced in the kidney cortex during CsA nephrotoxicity. Notably, the biomarkers of CsA nephrotoxicity associated with CsA have not been reviewed previously. Therefore, in this review, we will first provide an update on CsA nephrotoxicity in humans and describe the potential biomarkers of CsA nephrotoxicity. The molecular and cellular mechanisms that underlie CsA nephrotoxicity and the roles played by oxidative stress, autophagy, and signaling pathways will then be comprehensively summarized and discussed. Finally, the current therapeutical strategies for CsA nephrotoxcixity are summarized. We hope this review will provide a better understanding of CsA nephrotoxicity, thereby improving the management of patients who are treated with CsA.
环孢素 A（CsA）是一种广泛使用的免疫抑制剂，可大大降低肾、心和肝移植排斥的发生率。然而，CsA 肾毒性是一种严重的副作用，限制了 CsA 的临床应用。虽然 CsA 肾毒性的机制尚不完全清楚，但越来越多的证据表明氧化应激在这一现象中起重要作用。具体而言，CsA 诱导内质网应激并增加线粒体活性氧的产生：这改变了氧化还原平衡，导致脂质过氧化，从而诱导肾毒性。最近关于 CsA 肾毒性发病机制的研究表明，CsA 诱导的自噬可以减轻 CsA 诱导的内质网应激的有害影响，从而防止肾毒性物质引起的肾损伤。多种信号通路参与 CsA 肾毒性的发病机制。具体而言，p38、ERK 和 JNK MAPK 亚家族都参与了 CsA 肾毒性，而 NF-κB 是 CsA 的靶分子。此外，成纤维细胞因子 TGF-β1 有助于 CsA 诱导的肾纤维化，而 Nrf2 调节 CsA 诱导的细胞氧化应激。此外，CsA 通常抑制一氧化氮合成并损害肾动脉内皮依赖性松弛。然而，一些报道还表明，在 CsA 肾毒性期间，肾脏皮质中的一氧化氮合成增加。值得注意的是，与 CsA 相关的 CsA 肾毒性的生物标志物以前没有被综述过。因此，在本综述中，我们将首先提供人类 CsA 肾毒性的最新信息，并描述 CsA 肾毒性的潜在生物标志物。然后将全面总结和讨论 CsA 肾毒性的分子和细胞机制以及氧化应激、自噬和信号通路的作用。最后，总结了 CsA 肾毒性的当前治疗策略。我们希望本综述能更好地了解 CsA 肾毒性，从而改善接受 CsA 治疗的患者的管理。
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