title: Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2.
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.
authors.affiliation: Department of Nephrology, the Second Hospital of Jilin University, Changchun, Jilin, China, 130041; Kosair Children's Hospital Research Institute at the Department of Pediatrics, Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA, 40202.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Nephrology, the Second Hospital of Jilin University, Changchun, Jilin, China, 130041; Kosair Children's Hospital Research Institute at the Department of Pediatrics, Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA, 40202.
authors.forename: Lili
authors.initials: L
authors.lastname: Kong
authors.affiliation: Kosair Children's Hospital Research Institute at the Department of Pediatrics, Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA, 40202; The First Hospital of Jilin University, Changchun, Jilin, China, 130021.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Kosair Children's Hospital Research Institute at the Department of Pediatrics, Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA, 40202; The First Hospital of Jilin University, Changchun, Jilin, China, 130021.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, the Second Hospital of Jilin University, Changchun, Jilin, China, 130041.
authors.forename: Yangwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nephrology, the Second Hospital of Jilin University, Changchun, Jilin, China, 130041; Kosair Children's Hospital Research Institute at the Department of Pediatrics, Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA, 40202.
authors.forename: Manyu
authors.initials: M
authors.lastname: Luo
authors.affiliation: Kosair Children's Hospital Research Institute at the Department of Pediatrics, Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA, 40202; Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China, 325200.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Nephrology, Chinese PLA General Hospital, Beijing, China, 100853.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Nephrology, the Second Hospital of Jilin University, Changchun, Jilin, China, 130041. Electronic address: miaolining55@163.com.
authors.forename: Lining
authors.initials: L
authors.lastname: Miao
authors.affiliation: Kosair Children's Hospital Research Institute at the Department of Pediatrics, Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA, 40202; Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China, 325200. Electronic address: l0cai001@louisville.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000633:toxicity; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D017879:Isothiocyanates / Q000633:toxicity*; D008297:Male; D008668:Metallothionein / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013454:Sulfoxides
chemical_list: D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D013454:Sulfoxides; D008668:Metallothionein; C016766:sulforaphane
keywords: Diabetes; Fibrosis; Inflammation; Kidney; Oxidative stress