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      High Glucose Increases Metallothionein Expression in Renal Proximal Tubular Epithelial Cells

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          Abstract

          Metallothionein (MT) is an intracellular metal-binding, cysteine-rich protein, and is a potent antioxidant that protects cells and tissues from oxidative stress. Although the major isoforms MT-1 and -2 (MT-1/-2) are highly inducible in many tissues, the distribution and role of MT-1/-2 in diabetic nephropathy are poorly understood. In this study, diabetes was induced in adult male rats by streptozotocin, and renal tissues were stained with antibodies for MT-1/-2. MT-1/-2 expression was also evaluated in mProx24 cells, a mouse renal proximal tubular epithelial cell line, stimulated with high glucose medium and pretreated with the antioxidant vitamin E. MT-1/-2 expression was gradually and dramatically increased, mainly in the proximal tubular epithelial cells and to a lesser extent in the podocytes in diabetic rats, but was hardly observed in control rats. MT-1/-2 expression was also increased by high glucose stimulation in mProx24 cells. Because the induction of MT was suppressed by pretreatment with vitamin E, the expression of MT-1/-2 is induced, at least in part, by high glucose-induced oxidative stress. These observations suggest that MT-1/-2 is induced in renal proximal tubular epithelial cells as an antioxidant to protect the kidney from oxidative stress, and may offer a novel therapeutic target against diabetic nephropathy.

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          Most cited references26

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          Role of oxidative stress in diabetic complications: a new perspective on an old paradigm

          Oxidative stress and oxidative damage to tissues are common end points of chronic diseases, such as atherosclerosis, diabetes, and rheumatoid arthritis. The question addressed in this review is whether increased oxidative stress has a primary role in the pathogenesis of diabetic complications or whether it is a secondary indicator of end-stage tissue damage in diabetes. The increase in glycoxidation and lipoxidation products in plasma and tissue proteins suggests that oxidative stress is increased in diabetes. However, some of these products, such as 3-deoxyglucosone adducts to lysine and arginine residues, are formed independent of oxidation chemistry. Elevated levels of oxidizable substrates may also explain the increase in glycoxidation and lipoxidation products in tissue proteins, without the necessity of invoking an increase in oxidative stress. Further, age-adjusted levels of oxidized amino acids, a more direct indicator of oxidative stress, are not increased in skin collagen in diabetes. We propose that the increased chemical modification of proteins by carbohydrates and lipids in diabetes is the result of overload on metabolic pathways involved in detoxification of reactive carbonyl species, leading to a general increase in steady-state levels of reactive carbonyl compounds formed by both oxidative and nonoxidative reactions. The increase in glycoxidation and lipoxidation of tissue proteins in diabetes may therefore be viewed as the result of increased carbonyl stress. The distinction between oxidative and carbonyl stress is discussed along with the therapeutic implications of this difference.
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            Role of oxidative stress in diabetic complications: a new perspective on an old paradigm.

            Oxidative stress and oxidative damage to tissues are common end points of chronic diseases, such as atherosclerosis, diabetes, and rheumatoid arthritis. The question addressed in this review is whether increased oxidative stress has a primary role in the pathogenesis of diabetic complications or whether it is a secondary indicator of end-stage tissue damage in diabetes. The increase in glycoxidation and lipoxidation products in plasma and tissue proteins suggests that oxidative stress is increased in diabetes. However, some of these products, such as 3-deoxyglucosone adducts to lysine and arginine residues, are formed independent of oxidation chemistry. Elevated levels of oxidizable substrates may also explain the increase in glycoxidation and lipoxidation products in tissue proteins, without the necessity of invoking an increase in oxidative stress. Further, age-adjusted levels of oxidized amino acids, a more direct indicator of oxidative stress, are not increased in skin collagen in diabetes. We propose that the increased chemical modification of proteins by carbohydrates and lipids in diabetes is the result of overload on metabolic pathways involved in detoxification of reactive carbonyl species, leading to a general increase in steady-state levels of reactive carbonyl compounds formed by both oxidative and nonoxidative reactions. The increase in glycoxidation and lipoxidation of tissue proteins in diabetes may therefore be viewed as the result of increased carbonyl stress. The distinction between oxidative and carbonyl stress is discussed along with the therapeutic implications of this difference.
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              Metallothionein.

              Dean Hamer (1986)
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                Author and article information

                Journal
                Exp Diabetes Res
                EDR
                Experimental Diabetes Research
                Hindawi Publishing Corporation
                1687-5214
                1687-5303
                2011
                22 September 2011
                : 2011
                : 534872
                Affiliations
                1Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
                2Department of Diabetic Nephropathy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
                3Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
                4Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
                5CMIC Company, Ltd., Tokyo 113-0034, Japan
                6Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700-8558, Japan
                Author notes

                Academic Editor: Yasuhiko Tomino

                Article
                10.1155/2011/534872
                3179884
                21960990
                558003a7-7765-4684-a20c-7f1d32da1def
                Copyright © 2011 Daisuke Ogawa 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
                : 25 May 2011
                : 25 July 2011
                : 31 July 2011
                Categories
                Research Article

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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