PT  - JOURNAL ARTICLE
AU  - Entai Hou
AU  - Xuewei Zheng
AU  - Zhe Yang
AU  - Xian Li
AU  - Zerong Liu
AU  - Meng Chen
AU  - Xiaoxue Li
AU  - Mingyu Liang
AU  - Zhongmin Tian
TI  - Insufficient fumarase contributes to generating reactive oxygen species in Dahl salt sensitive rats
AID  - 10.1101/302182
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 302182
4099  - http://biorxiv.org/content/early/2018/04/16/302182.short
4100  - http://biorxiv.org/content/early/2018/04/16/302182.full
AB  - Dahl SS rats exhibit greater levels of renal medullary oxidative stress and lower levels of fumarase activities. Fumarase insufficiencies can increase reactive oxygen species (ROS), the mechanism of which, however, is not clear. A proteomic analysis indicated fumarase knockdown in HK-2 cells resulted in changes in the expression or activity of NADPH oxidase, mitochondrial respiratory chain complex I and III, ATP synthase subunits, and α-oxoglutarate dehydrogenase, all of which are sites of ROS formation. Meantime, the activities of key antioxidant enzymes such as G6PD, 6PGD, GR, GPx and GST increased significantly too. The apparent activation of antioxidant defense appeared insufficient as glutathione precursors, glutathione and GSH/GSSG ratio were decreased. SS rats exhibited changes in redox metabolism similar to HK-2 cells with fumarase knockdown. Supplementation with fumarate and malate, the substrate and product of fumarase, increased and decreased, respectively, blood pressure and the levels of H2O2 and MDA in kidney tissues of SS rats. These results indicate fumarase insufficiencies cause a wide range of changes at several sites of ROS production and antioxidant mechanisms.