Leukotrienes and kidney diseases

Abstract

Purpose of reviewThis 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.Recent findingsSince 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.SummaryCysteinyl 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.

The 5-Lipoxygenase Inhibitor Zileuton Protects Pressure Overload-Induced Cardiac Remodeling via Activating PPARα

“…In the past two decades, studies have focused on PGs and COX in determining the biological significance of AA and its metabolites. The effects of LTs on the cardiovascular system are now established [18, 19]. Both LTs and cysLTs are reported to be increased in failing hearts and contribute to the progression of heart failure [20–22].…”

Identification of an MGST2 gene and analysis of its function in antioxidant processes in Apis cerana cerana

“…MGST2 is widely recognized for its role in LTC4 synthesis (Sjöström et al, 2001). Therefore, more studies have shown that MGST2 is involved in the regulation of oxidative stress under stress responses in this situation (Rubinstein & Dvash, 2018). In recent years, it has also been found that the MGST2 gene is related to the occurrence of skin cancer, gastric cancer and other diseases (Wang et al, 2020; Yang et al, 2019; Zhang et al, 2019).…”

“…MGST2 triggers the expression of NADPH oxidase 4 via the MGST2‐LTC4‐cysLT1/2 pathway by regulating LTC4 synthesis, which causes the accumulation of ROS and oxidative damage (Rubinstein & Dvash, 2018). MPGES‐1, another member of the MAPEG family, can regulate mitochondrial oxidative stress by regulating the PGE2‐EP1/3‐JNK/ERK2 pathway through synthetic regulation of PGE2, and MAPKs are involved in this process (Avendaño et al, 2018).…”

“…In addition, transfection of Apostichopus japonicas MGST2 ( AjMGST2 ) small interfering RNA for 24 h has been found to increase the levels of ROS in cells by 40.1%, suggesting that AjMGST2 clears ROS (Zhang et al, 2017). Furthermore, a recent study has shown that cytotoxic substances trigger LTC4 synthesis by activating MGST2 to induce NADPH oxidase 4 expression, which then leads to the accumulation of ROS and oxidative stress (Rubinstein & Dvash, 2018).…”

The mercapturomic profile of health and non-communicable diseases

“…LTE4 mercapturate formation is mediated by NAT8 activity as described by the team of Veiga da Cunha (2010) [3]. CysTL are well known for their role in the pathophysiology of asthma and increasing evidence links these metabolites with non-communicable chronic inflammatory conditions [33,34], namely cardiovascular, neurologic and kidney disease [35] and cancer [36,37]. Altogether, non-communicable diseases represent the most common cause of death and multi-morbidity in the modern world [38].…”