Sodium butyrate activates NRF2 to ameliorate diabetic nephropathy possibly via inhibition of HDAC
- Wenpeng Dong1,2,
- Ye Jia3,
- Xiuxia Liu4,
- Huan Zhang5,
- Tie Li6,
- Wenlin Huang7,
- Xudong Chen8,
- Fuchun Wang6,
- Weixia Sun3⇑ and
- Hao Wu2,6⇑
- 1Dialysis Center, Daqing Oilfield General Hospital, Daqing, Heilongjiang, People’s Republic of China
- 2Department of Nephrology, The Second Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
- 3Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
- 4Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
- 5Operating theatre, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
- 6Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun, Jilin, People’s Republic of China
- 7School of Science and Technology, Georgia Gwinnett College, Lawrenceville, Georgia, USA
- 8Gastroenterology Department No. 1, Jilin Central General Hospital, Jilin, Jilin, People’s Republic of China
- Correspondence should be addressed to W Sun or H Wu; Email: sunweixia_78{at}163.com or wuhaobaha{at}yahoo.com, wuhaobaha{at}jlu.edu.cn
Abstract
Oxidative stress contributes to the pathogenesis of diabetic nephropathy (DN). Nuclear factor erythroid 2-related factor 2 (NRF2) plays a key role in cellular defense against oxidative stress. NRF2 activators have shown promising preventive effects on DN. Sodium butyrate (NaB) is a known activator of NRF2. However, it is unknown whether NRF2 is required for NaB protection against DN. Therefore, streptozotocin-induced diabetic C57BL/6 Nrf2 knockout and their wild-type mice were treated in the presence or absence of NaB for 20 weeks. Diabetic mice, but not NaB-treated diabetic mice, developed significant renal oxidative damage, inflammation, apoptosis, fibrosis, pathological changes and albuminuria. NaB inhibited histone deacetylase (HDAC) activity and elevated the expression of Nrf2 and its downstream targets heme oxygenase 1 and NAD(P)H dehydrogenase quinone 1. Notably, deletion of the Nrf2 gene completely abolished NaB activation of NRF2 signaling and protection against diabetes-induced renal injury. Interestingly, the expression of Kelch-like ECH-associated protein 1, the negative regulator of NRF2, was not altered by NaB under both diabetic and non-diabetic conditions. Moreover, NRF2 nuclear translocation was not promoted by NaB. Therefore, the present study indicates, for the first time, that NRF2 plays a key role in NaB protection against DN. Other findings suggest that NaB may activate Nrf2 at the transcriptional level, possibly by the inhibition of HDAC activity.
- Received 23 October 2016
- Accepted 25 October 2016
- Made available online as an Accepted Preprint 31 October 2016
- © 2017 Society for Endocrinology
