Insufficient fumarase contributes to hypertension by an imbalance of redox metabolism in Dahl salt-sensitive rats

Fumarase insufficiencies can increase reactive oxygen species (ROS). This study will further dissect the imbalance of redox metabolism and the mechanism of ROS production using proteomic technology in fumarase knockdown HK-2 cells. The contribution of fumarase was further confirmed by supplementation of fumarate and malate in Dahl salt-sensitive rats. Proteomic analysis indicated that fumarase knockdown in HK-2 cells changed the expression or activity of NADPH oxidase (NOX), mitochondrial respiratory chain Complex I and III, ATP synthase subunits, and α-oxoglutarate dehydrogenase (OGDH). Meanwhile, the activities of key antioxidant enzymes, including glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, increased significantly. The apparent activation of antioxidant defense appeared insufficient as the glutathione and GSH/GSSG ratio were decreased significantly. Dahl salt-sensitive rats exhibited changes in redox metabolism similar to HK-2 cells with fumarase knockdown. Supplementation with fumarate and malate increased and decreased, respectively, blood pressure and H₂O₂ and malondialdehyde in salt-sensitive rats. These results indicated that insufficient fumarase activity increased ROS by regulating NOX, Complex I and III, ATPase alpha, and OGDH and the imbalance of glutathione metabolism, which may be one of the main reasons for salt-sensitive hypertension. Malate may be a potentially effective drug for the prevention and treatment of salt-sensitive hypertension.