Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2 |
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| Affiliation: | 1. Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China;2. The Third Hospital of Hebei Medical University, China;1. Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan;2. Faculty of Science and Engineering, Setsunan University, 17-8 Ikedanaka-machi, Neyagawa, Osaka 572-8508, Japan;3. Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa, Kanazawa, 920-1181, Ishikawa, Japan;4. Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan;5. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan;6. Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan;1. Laboratory of Cardiovascular Physiology, Institute of Basic Health Science, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil;2. Centro Universitário Ritter dos Reis (Uniritter), Porto Alegre, Rio Grande do Sul, Brazil;3. Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil;4. Laboratório de Biologia Celular e Tecidual, Departamento de Ciências Morfofisiológicas, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil;5. Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada;6. Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada;1. Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA;2. Division of Brain Sciences, Imperial College London, London, United Kingdom;3. Department for General and Visceral Surgery, University Hospital Muenster, Muenster, Germany;4. Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom |
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| Abstract: | Sulforaphane (SFN) prevents diabetic nephropathy (DN) in type 1 diabetes via up-regulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, it has not been addressed whether SFN also prevents DN from type 2 diabetes or which Nrf2 downstream gene(s) play(s) the key role in SFN renal protection. Here we investigated whether Nrf2 is required for SFN protection against type 2 diabetes-induced DN and whether metallothionein (MT) is an Nrf2 downstream antioxidant using Nrf2 knockout (Nrf2-null) mice. In addition, MT knockout mice were used to further verify if MT is indispensable for SFN protection against DN. Diabetes-increased albuminuria, renal fibrosis, and inflammation were significantly prevented by SFN, and Nrf2 and MT expression was increased. However, SFN renal protection was completely lost in Nrf2-null diabetic mice, confirming the pivotal role of Nrf2 in SFN protection from type 2 diabetes-induced DN. Moreover, SFN failed to up-regulate MT in the absence of Nrf2, suggesting that MT is an Nrf2 downstream antioxidant. MT deletion resulted in a partial, but significant attenuation of SFN renal protection from type 2 diabetes, demonstrating a partial requirement for MT for SFN renal protection. Therefore, the present study demonstrates for the first time that as an Nrf2 downstream antioxidant, MT plays an important, though partial, role in mediating SFN renal protection from type 2 diabetes. |
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| Keywords: | Diabetes Kidney Oxidative stress Inflammation Fibrosis |
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