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      Crosstalk between the Unfolded Protein Response and NF- κB-Mediated Inflammation in the Progression of Chronic Kidney Disease

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          Abstract

          The chronic inflammatory response is emerging as an important therapeutic target in progressive chronic kidney disease. A key transcription factor in the induction of chronic inflammation is NF- κB. Recent studies have demonstrated that sustained activation of the unfolded protein response (UPR) can initiate this NF- κB signaling phenomenon and thereby induce chronic kidney disease progression. A key factor influencing chronic kidney disease progression is proteinuria and this condition has now been demonstrated to induce sustained UPR activation. This review details the crosstalk between the UPR and NF- κB pathways as pertinent to chronic kidney disease. We present potential tools to study this phenomenon as well as potential therapeutics that are emerging to regulate the UPR. These therapeutics may prevent inflammation specifically induced in the kidney due to proteinuria-induced sustained UPR activation.

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          Most cited references105

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          Endoplasmic reticulum stress: cell life and death decisions.

          C. Xu (2005)
          Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.
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            ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.

            ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis.
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              The impact of the unfolded protein response on human disease

              A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.
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                Author and article information

                Journal
                J Immunol Res
                J Immunol Res
                JIR
                Journal of Immunology Research
                Hindawi Publishing Corporation
                2314-8861
                2314-7156
                2015
                21 April 2015
                : 2015
                : 428508
                Affiliations
                Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, ON, Canada L8N 4A6
                Author notes
                *Jeffrey G. Dickhout: jdickhou@ 123456stjosham.on.ca

                Academic Editor: Oscar Bottasso

                Author information
                http://orcid.org/0000-0001-8436-0553
                Article
                10.1155/2015/428508
                4419235
                25977931
                84d5e2c4-5029-44c0-9537-1e4087125739
                Copyright © 2015 Zahraa Mohammed-Ali et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 July 2014
                : 4 September 2014
                Categories
                Review Article

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