Early postnatal treatment with soluble epoxide hydrolase inhibitor or 15-deoxy-Δ^12,14-prostagandin J₂ prevents prenatal dexamethasone and postnatal high saturated fat diet induced programmed hypertension in adult rat offspring

Prenatal dexamethasone (DEX) exposure, postnatal high-fat (HF) intake, and arachidonic acid pathway are closely related to hypertension. We tested whether a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-deoxy-Δ^12,14-prostagandin J₂ (15dPGJ₂) therapy can rescue programmed hypertension in the DEX + HF two-hit model. Four groups of Sprague Dawley rats were studied: control, DEX + HF, AUDA, and 15dPGJ₂. Dexamethasone (0.1 mg/kg body weight) was intraperitoneally administered to pregnant rats from gestational day 16-22. Male offspring received high-fat diet (D12331, Research Diets) from weaning to 4 months of age. In AUDA group, mother rats received 25 mg/L in drinking water during lactation. In the 15dPGJ₂ group, male offspring received 15dPGJ₂ 1.5 mg/kg BW by subcutaneous injection once daily for 1 week after birth. We found postnatal HF diet aggravated prenatal DEX-induced programmed hypertension, which was similarly prevented by early treatment with AUDA or 15dPGJ₂. The beneficial effects of AUDA and 15d-PGJ₂ therapy include inhibition of SEH, increases of renal angiotensin converting enzyme-2 (ACE2) and angiotensin II type 2 receptor (AT2R) protein levels, and restoration of nitric oxide bioavailability. Better understanding of the impact of arachidonic acid pathway in the two-hit model will help prevent programmed hypertension in children exposed to corticosteroids and postnatal HF intake.