Abstract
Consumption of food high in fructose and salt is associated with the epidemic of hypertension. Hypertension can originate from early life. Melatonin, a pleiotropic hormone, regulates blood pressure. We examined whether maternal melatonin therapy can prevent maternal high-fructose combined with post-weaning high-salt diet-induced programmed hypertension in adult offspring. Pregnant Sprague-Dawley rats received either a normal diet (ND) or a 60% fructose diet (HF) during pregnancy and the lactation period. Male offspring were on either the ND or a high-salt diet (HS, 1% NaCl) from weaning to 12 weeks of age and were assigned to five groups (n = 8/group): ND/ND, HF/ND, ND/HS, HF/HS, and HF/HS+melatonin. Melatonin (0.01% in drinking water) was administered during pregnancy and lactation. We observed that maternal HF combined with post-weaning HS diets induced hypertension in male adult offspring, which was attenuated by maternal melatonin therapy. The beneficial effects of maternal melatonin therapy on HF/HS-induced hypertension related to regulating several nutrient-sensing signals, including Sirt1, Sirt4, Prkaa2, Prkab2, Pparg, and Ppargc1a. Additionally, melatonin increased protein levels of mammalian targets of rapamycin (mTOR), decreased plasma asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine levels, and increased the l-arginine-to-ADMA ratio. The reprogramming effects by which maternal melatonin therapy protects against hypertension of developmental origin awaits further elucidation.
Highlights
Melatonin, a pineal indole hormone, has pleiotropic bioactivities, including regulating circadian rhythm, redox homeostasis, epigenetic regulation, glucose metabolism, anti-inflammation and anti-aging actions, and fetal development [1,2,3,4,5]
Our study provides new insight into how maternal melatonin therapy acts as part of a reprogramming strategy to prevent adult male offspring against programmed hypertension induced by maternal high fructose intake plus post-weaning high-salt diets
The key findings of our study can be summarized as follows: (1) maternal high-fructose diet combined with post-weaning high-salt diet caused hypertension in male adult offspring and maternal melatonin therapy was found to attenuate the development of hypertension in these offspring; (2) maternal melatonin therapy protects against HF/HS-induced hypertension, and is related to increased mRNA expression of Sirt1, Sirt4, Prkaa2, Prkab2, Pparg, and Ppargc1a in offspring kidneys; (3) high-salt diet reduced protein levels of AMPKα2, PGC-1α, mammalian targets of rapamycin (mTOR) and phosphorylated mTOR, whereas these decreases were restored by maternal melatonin therapy; and (4) maternal melatonin therapy restored the HF/HS-induced increases of plasma L-citrulline, asymmetric dimethylarginine (ADMA), and SDMA levels, and the decreases of L-arginine-to-ADMA
Summary
A pineal indole hormone, has pleiotropic bioactivities, including regulating circadian rhythm, redox homeostasis, epigenetic regulation, glucose metabolism, anti-inflammation and anti-aging actions, and fetal development [1,2,3,4,5]. The origins of susceptibility for hypertension in adults can be traced back to early life, formally named as the “developmental origins of health and disease” (DOHaD) [8]. Consumption of high-fructose (HF) diets by rodent mothers causes programmed hypertension in their adult offspring [13]. Our previous report showed that adult offspring of mothers exposed to 60% HF diet during pregnancy and lactation developed hypertension, which can be exacerbated by a post-weaning high-salt diet [14]. Whether maternal melatonin therapy is able to prevent programmed hypertension in adult offspring induced by maternal HF combined with post-weaning high-salt (HS) diets remains unknown
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