Maternal melatonin or N-acetylcysteine therapy regulates hydrogen sulfide-generating pathway and renal transcriptome to prevent prenatal N^G-Nitro-L-arginine-methyl ester (L-NAME)-induced fetal programming of hypertension in adult male offspring.

Abstract

Pregnancy is a critical time for fetal programming of hypertension. Nitric oxide deficiency during pregnancy causes hypertension in adult offspring. We examined whether maternal melatonin or N-acetylcysteine therapy can prevent N^G-nitro-L-arginine-methyl ester-induced fetal programming of hypertension in adult offspring. Next, we aimed to identify potential gatekeeper pathways that contribute to N^G-nitro-L-arginine-methyl ester -induced programmed hypertension using the next generation RNA sequencing technology. Pregnant Sprague-Dawley rats were assigned to 4 groups: control, N^G-nitro-L-arginine-methyl ester, N^G-nitro-L-arginine-methyl ester +melatonin, and N^G-nitro-L-arginine-methyl ester+N-acetylcysteine. Pregnant rats received N^G-nitro-L-arginine-methyl ester administration at 60 mg/kg/d subcutaneously during pregnancy alone, with additional 0.01% melatonin in drinking water, or with additional 1% N-acetylcysteine in drinking water during the entire pregnancy and lactation. Male offspring (n=8/group) were killed at 12 weeks of age. N^G-nitro-L-arginine-methyl ester exposure during pregnancy induced programmed hypertension in adult male offspring, which was prevented by maternal melatonin or N-acetylcysteine therapy. Protective effects of melatonin and N-acetylcysteine against N^G-nitro-L-arginine-methyl ester-induced programmed hypertension were associated with an increase in hydrogen sulfide-generating enzymes and hydrogen sulfide synthesis in the kidneys. Nitric oxide inhibition by N^G-nitro-L-arginine-methyl ester in pregnancy caused >2000 renal transcripts to be modified during nephrogenesis stage in 1-day-old offspring kidney. Among them, genes belong to the renin-angiotensin system, and arachidonic acid metabolism pathways were potentially involved in the N^G-nitro-L-arginine-methyl ester-induced programmed hypertension. However, melatonin and N-acetylcysteine reprogrammed the renin-angiotensin system and arachidonic acid pathway differentially. Our results indicated that antioxidant therapy, by melatonin or N-acetylcysteine, in pregnant rats with nitric oxide deficiency can prevent programmed hypertension in male adult offspring. Early intervention with specific antioxidants that target redox imbalance in pregnancy to reprogram hypertension may well allow us to reduce the future burden of hypertension. The roles of transcriptome changes that are induced by N^G-nitro-L-arginine-methyl ester in the offspring kidney require further clarification.