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Free Radic Biol Med. 2015 Dec;89:431-42. doi: 10.1016/j.freeradbiomed.2015.08.009. Epub 2015 Sep 28.

Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2.

Author information

1
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.
2
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.
3
Department of Nephrology, the Second Hospital of Jilin University, Changchun, Jilin, China, 130041.
4
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.
5
Department of Nephrology, Chinese PLA General Hospital, Beijing, China, 100853.
6
Department of Nephrology, the Second Hospital of Jilin University, Changchun, Jilin, China, 130041. Electronic address: miaolining55@163.com.
7
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.

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.

KEYWORDS:

Diabetes; Fibrosis; Inflammation; Kidney; Oxidative stress

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