Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
Curr Opin Nephrol Hypertens. 2018 Jan;27(1):42-48. doi: 10.1097/MNH.0000000000000381.
This review will critically highlight the role of leukotrienes as mediators of renal diseases and drug nephrotoxicity. It will also discuss the recently identified mechanism of cysteinyl leukotrienes induction and action, and will propose clinical implementation of these findings.
Since last reviewed in 1994, leukotrienes were shown to mediate drug-associated nephrotoxicity, transplant rejection and morbidity in several models of renal diseases. Although leukotrienes may be released by various infiltrating leukocytes, a recent study demonstrated that cytotoxic agents trigger production of leukotriene C4 (LTC4) in mouse kidney cells by activating a biosynthetic pathway based on microsomal glutathione-S-transferase 2 (MGST2). LTC4 then elicits nuclear accumulation of hydrogen peroxide-generating NADPH oxidase 4, leading to oxidative DNA damage and cell death. LTC4 inhibitors, commonly used as systemic asthma drugs, alleviated drug-associated damage to proximal tubular cells and attenuated mouse morbidity.
Cysteinyl leukotrienes released by mast cells trigger the symptoms of asthma, including bronchoconstriction and vasoconstriction. Therefore, effective leukotriene inhibitors were approved as orally administered asthma drugs. The findings that leukotrienes mediate the cytotoxicity of nephrotoxic drugs, and are involved in numerous renal diseases, suggest that such asthma drugs may ameliorate drug-induced nephrotoxicity, as well as some renal diseases.
本文批判性地强调了白三烯作为肾脏疾病和药物肾毒性的介质的作用。本文还将讨论新近发现的半胱氨酰白三烯诱导和作用机制，并提出这些发现的临床应用。
自 1994 年上次综述以来，白三烯被证明在几种肾脏疾病模型中介导药物相关性肾毒性、移植排斥和发病率。尽管白三烯可能由各种浸润性白细胞释放，但最近的一项研究表明，细胞毒性药物通过激活基于微粒体谷胱甘肽-S-转移酶 2（MGST2）的生物合成途径，在小鼠肾细胞中触发白三烯 C4（LTC4）的产生。然后，LTC4 引发产生过氧化氢的 NADPH 氧化酶 4 的核积累，导致氧化 DNA 损伤和细胞死亡。LTC4 抑制剂，通常用作全身哮喘药物，减轻了近端肾小管细胞的药物相关性损伤，并减轻了小鼠的发病率。
肥大细胞释放的半胱氨酰白三烯引发哮喘症状，包括支气管收缩和血管收缩。因此，有效的白三烯抑制剂被批准为口服哮喘药物。白三烯介导肾毒性药物的细胞毒性，以及涉及多种肾脏疾病的发现表明，这种哮喘药物可能改善药物引起的肾毒性以及某些肾脏疾病。
