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      Tempol Attenuates Renal Fibrosis in Mice with Unilateral Ureteral Obstruction: The Role of PI3K-Akt-FoxO3a Signaling

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          Abstract

          This study investigated whether tempol, an anti-oxidant, protects against renal injury by modulating phosphatidylinositol 3-kinase (PI3K)-Akt-Forkhead homeobox O (FoxO) signaling. Mice received unilateral ureteral obstruction (UUO) surgery with or without administration of tempol. We evaluated renal damage, oxidative stress and the expression of PI3K, Akt, FoxO3a and their target molecules including manganese superoxide dismutase (MnSOD), catalase, Bax, and Bcl-2 on day 3 and day 7 after UUO. Tubulointerstitial fibrosis, collagen deposition, α-smooth muscle actin-positive area, and F4/80-positive macrophage infiltration were significantly lower in tempol-treated mice compared with control mice. The expression of PI3K, phosphorylated Akt, and phosphorylated FoxO3a markedly decreased in tempol-treated mice compared with control mice. Tempol prominently increased the expressions of MnSOD and catalase, and decreased the production of hydrogen peroxide and lipid peroxidation in the obstructed kidneys. Significantly less apoptosis, a lower ratio of Bax to Bcl-2 expression and fewer apoptotic cells in TUNEL staining, and decreased expression of transforming growth factor-β1 were observed in the obstructed kidneys from tempol-treated mice compared with those from control mice. Tempol attenuates oxidative stress, inflammation, and fibrosis in the obstructed kidneys of UUO mice, and the modulation of PI3K-Akt-FoxO3a signaling may be involved in this pathogenesis.

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          Most cited references22

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          Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.

          Bcl-2 protein is able to repress a number of apoptotic death programs. To investigate the mechanism of Bcl-2's effect, we examined whether Bcl-2 interacted with other proteins. We identified an associated 21 kd protein partner, Bax, that has extensive amino acid homology with Bcl-2, focused within highly conserved domains I and II. Bax is encoded by six exons and demonstrates a complex pattern of alternative RNA splicing that predicts a 21 kd membrane (alpha) and two forms of cytosolic protein (beta and gamma). Bax homodimerizes and forms heterodimers with Bcl-2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of Bcl-2. These data suggest a model in which the ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus.
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            Akt, FoxO and regulation of apoptosis.

            Forkhead box O (FoxO) transcription factors are downstream targets of the serine/threonine protein kinase B (PKB)/Akt. The Akt kinase regulates processes of cellular proliferation and survival. Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation. Emerging evidence suggests involvement of FoxOs in diverse intracellular signaling pathways with critical roles in a number of physiological as well as pathological conditions including cancer. The FoxO signaling is regulated by their interactions with other intracellular proteins as well as their post-translational modifications such as phosphorylation. FoxOs promote cell growth inhibitory and/or apoptosis signaling by either inducing expression of multiple pro-apoptotic members of the Bcl2-family of mitochondria-targeting proteins, stimulating expression of death receptor ligands such as Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), or enhancing levels of various cyclin-dependent kinase inhibitors (CDKIs). Coupled with their ability to cross-talk with p53, FoxOs represent an important class of tumor suppressors in a variety of cancers. This review summarizes our current understanding of mechanisms by which Akt and FoxOs regulate cell growth and survival that in turn offers opportunities for development of novel strategies to combat cancer. This article is part of a Special Issue entitled: P13K-AKT-FOxO axis in cancer and aging. 2011 Elsevier B.V. All rights reserved.
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              Stressing the role of FoxO proteins in lifespan and disease.

              Members of the class O of forkhead box transcription factors (FoxO) have important roles in metabolism, cellular proliferation, stress tolerance and probably lifespan. The activity of FoxOs is tightly regulated by post-translational modifications, including phosphorylation, acetylation and ubiquitylation. Several of the enzymes that regulate the turnover of these post-translational modifications are shared between FoxO and p53. These regulatory enzymes affect FoxO and p53 function in an opposite manner. This shared yet opposing regulatory network between FoxOs and p53 may underlie a 'trade-off' between disease and lifespan.
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                Author and article information

                Journal
                J Korean Med Sci
                J. Korean Med. Sci
                JKMS
                Journal of Korean Medical Science
                The Korean Academy of Medical Sciences
                1011-8934
                1598-6357
                February 2014
                28 January 2014
                : 29
                : 2
                : 230-237
                Affiliations
                [1 ]Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
                [2 ]Division of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, Incheon, Korea.
                Author notes
                Address for Correspondence: Seok Joon Shin, MD. Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 56 Dongsu-ro, Bupyeoung-gu, Incheon 403-720, Korea. Tel: +82.32-280-5091, Fax: +82.32-280-5987, imkidney@ 123456catholic.ac.kr
                Author information
                http://orcid.org/0000-0002-6347-7282
                http://orcid.org/0000-0001-7642-2849
                Article
                10.3346/jkms.2014.29.2.230
                3924002
                24550650
                fba6516c-fae8-4896-b624-5ef5d4479361
                © 2014 The Korean Academy of Medical Sciences.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 August 2013
                : 29 November 2013
                Funding
                Funded by: National Research Foundation
                Award ID: 20110013312
                Funded by: Catholic Medical Center
                Award ID: 52011B000100001
                Funded by: Incheon St. Mary's Hospital
                Award ID: 52012B000100138
                Categories
                Original Article
                Nephrology

                Medicine
                oxidative stress,unilateral ureteral obstruction,renal fibrosis,apoptosis,foxo3a protein, mouse

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