title: Sodium butyrate activates NRF2 to ameliorate diabetic nephropathy possibly via inhibition of HDAC.
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.
authors: Dialysis CenterDaqing Oilfield General Hospital, Daqing, Heilongjiang, People's Republic of China.|Department of NephrologyThe Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
authors: Wenpeng
authors: W
authors: Dong
authors: Department of NephrologyThe First Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
authors: Ye
authors: Y
authors: Jia
authors: Department of Clinical LaboratoryThe Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
authors: Xiuxia
authors: X
authors: Liu
authors: Operating theatreChina-Japan Union Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
authors: Huan
authors: H
authors: Zhang
authors: Department of Acupuncture and TuinaChangchun University of Chinese Medicine, Changchun, Jilin, People's Republic of China.
authors: Tie
authors: T
authors: Li
authors: School of Science and TechnologyGeorgia Gwinnett College, Lawrenceville, Georgia, USA.
authors: Wenlin
authors: W
authors: Huang
authors: Gastroenterology Department No. 1Jilin Central General Hospital, Jilin, Jilin, People's Republic of China.
authors: Xudong
authors: X
authors: Chen
authors: Department of Acupuncture and TuinaChangchun University of Chinese Medicine, Changchun, Jilin, People's Republic of China.
authors: Fuchun
authors: F
authors: Wang
authors: Department of NephrologyThe First Hospital of Jilin University, Changchun, Jilin, People's Republic of China sunweixia_78@163.com
authors: Weixia
authors: W
authors: Sun
authors: Department of Acupuncture and TuinaChangchun University of Chinese Medicine, Changchun, Jilin, People's Republic of China.|Department of NephrologyThe Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China wuhaobaha@yahoo.com wuhaobaha@jlu.edu.cn.
authors: Hao
authors: H
authors: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020148:Butyric Acid / Q000494:pharmacology / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D020148:Butyric Acid; D006655:Histone Deacetylases
keywords: HDAC; KEAP1; NaB; diabetes; oxidative stress