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      Leukotrienes and kidney diseases

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          Abstract

          Purpose of review

          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.

          Recent 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 C 4 (LTC 4) in mouse kidney cells by activating a biosynthetic pathway based on microsomal glutathione-S-transferase 2 (MGST2). LTC 4 then elicits nuclear accumulation of hydrogen peroxide-generating NADPH oxidase 4, leading to oxidative DNA damage and cell death. LTC 4 inhibitors, commonly used as systemic asthma drugs, alleviated drug-associated damage to proximal tubular cells and attenuated mouse morbidity.

          Summary

          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.

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          Most cited references40

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          Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7.

          The endogenous ligands for the LT, lipoxin (LX) and oxoeicosanoid receptors are bioactive products produced by the action of the lipoxygenase family of enzymes. The LT receptors BLT1 and BLT2 , are activated by LTB4 and the CysLT1 and CysLT2 receptors are activated by the cysteinyl-LTs, whereas oxoeicosanoids exert their action through the OXE receptor. In contrast to these pro-inflammatory mediators, LXA4 transduces responses associated with the resolution of inflammation through the receptor FPR2/ALX (ALX/FPR2). The aim of the present review is to give a state of the field on these receptors, with focus on recent important findings. For example, BLT1 receptor signalling in cancer and the dual role of the BLT2 receptor in pro- and anti-inflammatory actions have added more complexity to lipid mediator signalling. Furthermore, a cross-talk between the CysLT and P2Y receptor systems has been described, and also the presence of novel receptors for cysteinyl-LTs, such as GPR17 and GPR99. Finally, lipoxygenase metabolites derived from ω-3 essential polyunsaturated acids, the resolvins, activate the receptors GPR32 and ChemR23. In conclusion, the receptors for the lipoxygenase products make up a sophisticated and tightly controlled system of endogenous pro- and anti-inflammatory signalling in physiology and pathology.
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            Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage

            Endoplasmic reticulum (ER) stress and major chemotherapeutic agents damage DNA by generating reactive oxygen species (ROS). Here we show that ER stress and chemotherapy induce leukotriene C4 (LTC4) biosynthesis by transcriptionally upregulating and activating the enzyme microsomal glutathione-S-transferase 2 (MGST2) in cells of non-haematopoietic lineage. ER stress and chemotherapy also trigger nuclear translocation of the two LTC4 receptors. Acting in an intracrine manner, LTC4 then elicits nuclear translocation of NADPH oxidase 4 (NOX4), ROS accumulation and oxidative DNA damage. Mgst2 deficiency, RNAi and LTC4 receptor antagonists abolish ER stress- and chemotherapy-induced ROS and oxidative DNA damage in vitro and in mouse kidneys. Cell death and mouse morbidity are also significantly attenuated. Hence, MGST2-generated LTC4 is a major mediator of ER stress- and chemotherapy-triggered oxidative stress and oxidative DNA damage. LTC4 inhibitors, commonly used for asthma, could find broad clinical use in major human pathologies associated with ER stress-activated NOX4.
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              The leukotrienes: immune-modulating lipid mediators of disease.

              The leukotrienes are important lipid mediators with immune modulatory and proinflammatory properties. Classical bioactions of leukotrienes include chemotaxis, endothelial adherence, and activation of leukocytes, chemokine production, as well as contraction of smooth muscles in the microcirculation and respiratory tract. When formed in excess, these compounds play a pathogenic role in several acute and chronic inflammatory diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel disease. An increasing number of diseases have been linked to inflammation implicating the leukotrienes as potential mediators. For example, recent investigations using genetic, morphological, and biochemical approaches have pointed to the involvement of leukotrienes in cardiovascular diseases including atherosclerosis, myocardial infarction, stroke, and abdominal aortic aneurysm. Moreover, new insights have changed our previous notion of leukotrienes as mediators of inflammatory reactions to molecules that can fine-tune the innate and adaptive immune response. Here, we review the most recent understanding of the leukotriene cascade with emphasis on recently identified roles in immune reactions and pathophysiology. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Curr Opin Nephrol Hypertens
                Curr. Opin. Nephrol. Hypertens
                CONHY
                Current Opinion in Nephrology and Hypertension
                Lippincott Williams & Wilkins
                1062-4821
                1473-6543
                January 2018
                07 November 2017
                : 27
                : 1
                : 42-48
                Affiliations
                Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
                Author notes
                Correspondence to Menachem Rubinstein, PhD, Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 7610001, Israel. Tel: +972 8 934 2313; e-mail: Menachem.Rubinstein@ 123456weizmann.ac.il
                Article
                270104 00008
                10.1097/MNH.0000000000000381
                5732635
                29059080
                beaf61fa-4f69-4d11-b1ad-b7be3c3e24d7
                Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                Categories
                HORMONES, AUTACOIDS, NEUROTRANSMITTERS AND GROWTH FACTORS: Edited by Mark Cooper and Merlin Thomas
                Custom metadata
                TRUE

                drug-associated toxicity,leukotriene c4,microsomal glutathione-s-transferase 2,nadph oxidase 4

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