Activation of Nuclear Factor Erythroid 2-Related Factor 2 Coordinates Dimethylarginine Dimethylaminohydrolase/PPAR-gamma/Endothelial Nitric Oxide Synthase Pathways That Enhance Nitric Oxide Generation in Human Glomerular Endothelial Cells

作者：Luo Zaiming; Aslam Shakil; Welch William J; Wilcox Christopher S^*

来源：Hypertension, 2015, 65(4): 896-+.

DOI：10.1161/HYPERTENSIONAHA.114.04760

• 2-tert-butylhydroquinone
• antioxidant response elements

Dimethylarginine dimethylaminohydrolase (DDAH) degrades asymmetric dimethylarginine, which inhibits nitric oxide (NO) synthase (NOS). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that binds to antioxidant response elements and transcribes many antioxidant genes. Because the promoters of the human DDAH-1 and DDAH-2, endothelial NOS (eNOS) and PPAR-gamma genes contain 2 to 3 putative antioxidant response elements, we hypothesized that they were regulated by Nrf2/antioxidant response element. Incubation of human renal glomerular endothelial cells with the Nrf2 activator tert-butylhydroquinone (20 mu mol.L-1) significantly (P<0.05) increased NO and activities of NOS and DDAH and decreased asymmetric dimethylarginine. It upregulated genes for hemoxygenase-1, eNOS, DDAH-1, DDAH-2, and PPAR-gamma and partitioned Nrf2 into the nucleus. Knockdown of Nrf2 abolished these effects. Nrf2 bound to one antioxidant response element on DDAH-1 and DDAH-2 and PPAR-gamma promoters but not to the eNOS promoter. An increased eNOS and phosphorylated eNOS (P-eNOSser-1177) expression with tert-butylhydroquinone was prevented by knockdown of PPAR-gamma. Expression of Nrf2 was reduced by knockdown of PPAR-gamma, whereas PPAR-gamma was reduced by knockdown of Nrf2, thereby demonstrating 2-way positive interactions. Thus, Nrf2 transcribes HO-1 and other genes to reduce reactive oxygen species, and DDAH-1 and DDAH-2 to reduce asymmetric dimethylarginine and PPAR-gamma to increase eNOS and its phosphorylation and activity thereby coordinating 3 pathways that enhance endothelial NO generation.

• 出版日期2015-4