Protection of Male Rat Offspring against Hypertension Programmed by Prenatal Dexamethasone Administration and Postnatal High-Fat Diet with the Nrf2 Activator Dimethyl Fumarate during Pregnancy

• Main Authors: Chien-Ning Hsu, Yu-Ju Lin, Hong-Ren Yu, I-Chun Lin, Jiunn-Ming Sheen, Li-Tung Huang, You-Lin Tain
• Format: Article
• Language: English
• Published: MDPI AG 2019-08-01
• Series: International Journal of Molecular Sciences
• Subjects: asymmetric dimethylarginine; developmental origins of health and disease (DOHaD); hypertension; nuclear factor erythroid-derived 2-related factor 2 (Nrf2); nitric oxide; nutrient sensing signal; oxidative stress; renin-angiotensin system
• Online Access: https://www.mdpi.com/1422-0067/20/16/3957

Hypertension can originate from early-life exposure to oxidative stress. As reported, dimethyl fumarate (DMF) activates nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and protects against oxidative stress damage. We examined whether maternal DMF therapy protects adult offspring against hypertension programmed by prenatal dexamethasone (DEX) and postnatal high-fat (HF) diet exposure. We examined male Sprague Dawley rat offspring at 4 months of age from five groups (<i>n</i> = 11&#8722;13/group): control, DEX (0.1mg/kg i.p. from gestational day 16 to 22), HF (D12331 diet from weaning to 16 weeks of age), DEX+HF, and DEX+HF+DMF (50mg/kg/day via gastric gavage for 3 weeks during pregnancy). Maternal DMF therapy prevented male offspring against hypertension programmed by combined DEX and HF exposures. The protective effects of maternal DMF include reduced oxidative stress, decreased plasma asymmetric dimethylarginine (ADMA) levels, downregulated the renin-angiotensin system (i.e. <i>Ren</i>, <i>Agt</i>, <i>Ace</i>, and <i>Agtr1a</i>), increased renal protein levels of certain nutrient-sensing signals, and promoted autophagy. In conclusion, maternal Nrf2 activation by DMF protects male adult offspring against hypertension programmed by combined DEX and HF exposures. Our results cast a new light on the therapeutic potential of targeting Nrf2 signaling pathway as reprogramming strategies to prevent programmed hypertension in children exposed to antenatal corticosteroids and postnatally excessive consumption of fat.