title: Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats.
abstract: The master transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of antioxidant and phase II-metabolizing enzymes by activating the antioxidant response element (ARE) and thereby protects cells and tissues from oxidative stress. Pulmonary complications remain the leading cause of death in human immunodeficiency virus (HIV)-1-infected individuals, who display systemic oxidative stress and glutathione deficiency that can be modeled in transgenic rats where HIV-1-related viral proteins decrease glutathione levels and cause epithelial barrier dysfunction within the alveolar space by as yet unknown mechanisms. We hypothesized that HIV-1-related proteins inhibit Nrf2-mediated antioxidant defenses and thereby disrupt the normally tight alveolar epithelial barrier. Nrf2 RNA silencing dampened Nrf2/ARE activity, decreased the expression of the tight junction proteins zonula occludens-1, occludin, and claudin-18, increased paracellular permeability of alveolar epithelial monolayers derived from wild-type rats, and therefore reproduced the effects of HIV-1 transgene expression on the epithelial barrier that we had previously described. In contrast, upregulating Nrf2 activity, either by plasmid-mediated overexpression or treatment with the Nrf2 activator sulforaphane, increased the expression of ARE-dependent antioxidants, including NAD(P)H dehydrogenase, quinone 1 and glutathione, improved the expression of tight junction proteins, and restored the ability to form tight barriers in alveolar epithelial cells from HIV-1 transgenic rats. Taken together, these new findings argue that HIV-1-related proteins downregulate Nrf2 expression and/or activity within the alveolar epithelium, which in turn impairs antioxidant defenses and barrier function, thereby rendering the lung susceptible to oxidative stress and injury. Furthermore, this study suggests that activating the Nrf2/ARE pathway with the dietary supplement sulforaphane could augment antioxidant defenses and lung health in HIV-1-infected individuals.
authors.affiliation: Division of Pulmonary, Allergy & Critical Care Medicine, Emory University School of Medicine, 615 Michael St., Ste. 205, Atlanta, GA 30322, USA. xfan@emory.edu
authors.forename: Xian
authors.initials: X
authors.lastname: Fan
authors.forename: Bashar S
authors.initials: BS
authors.lastname: Staitieh
authors.forename: J Spencer
authors.initials: JS
authors.lastname: Jensen
authors.forename: Kara J
authors.initials: KJ
authors.lastname: Mould
authors.forename: Jared A
authors.initials: JA
authors.lastname: Greenberg
authors.forename: Pratibha C
authors.initials: PC
authors.lastname: Joshi
authors.forename: Michael
authors.initials: M
authors.lastname: Koval
authors.forename: David M
authors.initials: DM
authors.lastname: Guidot
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D061745:Antioxidant Response Elements / Q000502:physiology*; D002478:Cells, Cultured; D057167:Claudins / Q000378:metabolism; D015536:Down-Regulation; D005978:Glutathione / Q000032:analysis / Q000096:biosynthesis; D015497:HIV-1 / Q000378:metabolism*; D017879:Isothiocyanates; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D062793:Occludin / Q000378:metabolism; D018384:Oxidative Stress; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011809:Quinones / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger; D051381:Rats; D055647:Rats, Transgenic; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D062725:Tight Junction Proteins / Q000096:biosynthesis; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D057167:Claudins; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D062793:Occludin; D011809:Quinones; D012333:RNA, Messenger; D013454:Sulfoxides; D013861:Thiocyanates; D062725:Tight Junction Proteins; D062826:Zonula Occludens-1 Protein; D016660:NAD(P)H Dehydrogenase (Quinone); C016766:sulforaphane; D005978:Glutathione
keywords: epithelial barrier function; human immunodeficiency virus-1 transgene; nuclear factor (erythroid-derived 2)-like 2; sulforaphane; tight junction protein