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      Long-Term Treatment with the Sodium Glucose Cotransporter 2 Inhibitor, Dapagliflozin, Ameliorates Glucose Homeostasis and Diabetic Nephropathy in db/db Mice

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          Abstract

          Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic β-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-β, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, β-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.

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          Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy.

          Many lines of evidence, ranging from in vitro experiments and pathological examinations to epidemiological studies, show that inflammation is a cardinal pathogenetic mechanism in diabetic nephropathy. Thus, modulation of inflammatory processes in the setting of diabetes mellitus is a matter of great interest for researchers today. The relationships between inflammation and the development and progression of diabetic nephropathy involve complex molecular networks and processes. This Review, therefore, focuses on key proinflammatory molecules and pathways implicated in the development and progression of diabetic nephropathy: the chemokines CCL2, CX3CL1 and CCL5 (also known as MCP-1, fractalkine and RANTES, respectively); the adhesion molecules intercellular adhesion molecule 1, vascular cell adhesion protein 1, endothelial cell-selective adhesion molecule, E-selectin and α-actinin 4; the transcription factor nuclear factor κB; and the inflammatory cytokines IL-1, IL-6, IL-18 and tumor necrosis factor. Advances in the understanding of the roles that these inflammatory pathways have in the context of diabetic nephropathy will facilitate the discovery of new therapeutic targets. In the next few years, promising new therapeutic strategies based on anti-inflammatory effects could be successfully translated into clinical treatments for diabetic complications, including diabetic nephropathy.
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            A glimpse of various pathogenetic mechanisms of diabetic nephropathy.

            Diabetic nephropathy is a well-known complication of diabetes and is a leading cause of chronic renal failure in the Western world. It is characterized by the accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments and by the thickening and hyalinization of intrarenal vasculature. The various cellular events and signaling pathways activated during diabetic nephropathy may be similar in different cell types. Such cellular events include excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products, activation of protein kinase C, increased expression of transforming growth factor β and GTP-binding proteins, and generation of reactive oxygen species. In addition to these metabolic and biochemical derangements, changes in the intraglomerular hemodynamics, modulated in part by local activation of the renin-angiotensin system, compound the hyperglycemia-induced injury. Events involving various intersecting pathways occur in most cell types of the kidney.
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              SGLT2 inhibition--a novel strategy for diabetes treatment.

              Inhibiting sodium-glucose co-transporters (SGLTs), which have a key role in the reabsorption of glucose in the kidney, has been proposed as a novel therapeutic strategy for diabetes. Genetic mutations in the kidney-specific SGLT2 isoform that result in benign renal glycosuria, as well as preclinical and clinical studies with SGLT2 inhibitors in type 2 diabetes, support the potential of this approach. These investigations indicate that elevating renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as decrease weight. Although data from ongoing Phase III trials of these agents are needed to more fully assess safety, results suggest that the beneficial effects of SGLT2 inhibition might be achieved without exerting significant side effects--an advantage over many current diabetes medications. This article discusses the role of SGLT2 in glucose homeostasis and the evidence available so far on the therapeutic potential of blocking these transporters in the treatment of diabetes.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                24 June 2014
                : 9
                : 6
                : e100777
                Affiliations
                [1 ]Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
                [2 ]Department of Diabetic Nephropathy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
                [3 ]Department of Neurochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
                Hirosaki University Graduate School of Medicine, Japan
                Author notes

                Competing Interests: D. Ogawa belongs to the Department of Diabetic Nephropathy, which is endowed by Boehringer Ingelheim. J. Wada is a consultant for Boehringer Ingelheim and receives speaker honoraria from Novartis. H. Makino is a consultant for AbbVie, Astellas and Teijin, receives speaker honoraria from Astellas, Boehringer-ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novartis, Pfizer, Takeda, and Tanabe Mitsubishi, and receives grant support from Astellas, Boehringer-ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, Mochida, MSD, Novartis, Novo Nordisk, Pfizer, Takeda, and Tanabe Mitsubishi. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: DO. Performed the experiments: NT DO HT TH CSH. Analyzed the data: JW AN JE NN HY. Wrote the paper: DO KT HM.

                Article
                PONE-D-13-54005
                10.1371/journal.pone.0100777
                4069074
                24960177
                2776fb8d-6afe-459a-9aad-957e4fd197b8
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 December 2013
                : 29 May 2014
                Page count
                Pages: 13
                Funding
                This study was supported in part by Grant-in-Aid for Scientific Research (C) to D. Ogawa (25461223) and Grant-in-Aid for Young Scientists (B) to C. Sato Horiguchi (24790927) from the Ministry of Education, Culture, Sports, Science and Technology, and by Grant-in-Aid for Diabetic Nephropathy and Nephrosclerosis Research from the Ministry of Health, Labour and Welfare of Japan. This work was also supported by the Naito Foundation and the Takeda Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Endocrinology
                Diabetic Endocrinology
                Metabolic Disorders
                Diabetes Mellitus
                Type 2 Diabetes
                Nephrology
                Chronic Kidney Disease

                Uncategorized
                Uncategorized

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