Abstract
Widespread consumption of a Western diet, comprised of highly refined carbohydrates and fat, may play a role in the epidemic of hypertension. Hypertension can take origin from early life. Metformin is the preferred treatment for type 2 diabetes. We examined whether prenatal metformin therapy can prevent maternal high-fructose plus post-weaning high-fat diets-induced hypertension of developmental origins via regulation of nutrient sensing signals, uric acid, oxidative stress, and the nitric oxide (NO) pathway. Gestating Sprague–Dawley rats received regular chow (ND) or chow supplemented with 60% fructose diet (HFR) throughout pregnancy and lactation. Male offspring were onto either the ND or high-fat diet (HFA) from weaning to 12 weeks of age. A total of 40 male offspring were assigned to five groups (n = 8/group): ND/ND, HFR/ND, ND/HFA, HFR/HFA, and HFR/HFA+metformin. Metformin (500 mg/kg/day) was administered via gastric gavage for three weeks during the pregnancy period. Combined maternal HFR plus post-weaning HFA induced hypertension in male adult offspring, which prenatal metformin therapy prevented. The protective effects of prenatal metformin therapy on HFR/HFA-induced hypertension, including downregulation of the renin-angiotensin system, decrease in uric acid level, and reduction of oxidative stress. Our results highlighted that the programming effects of metformin administered prenatally might be different from those reported in adults, and that deserves further elucidation.
Highlights
Metformin (1,1-dimethylbiguanide hydrochloride) is the favorite first-line oral blood glucose-lowering treatment for type 2 diabetes [1]
The major findings in this study are: (1) combined maternal high-fructose plus post-weaning high-fat diets induced hypertension in adult male offspring, which prenatal metformin therapy prevented; (2) HFR/HFA induced hypertension relates to alterations in the nutrient sensing signals, uric acid, oxidative stress, nitric oxide (NO) pathway, and renin-angiotensin system (RAS); (3) in HFR/HFA-induced programmed hypertension, downregulation of the RAS, decreases in uric acid level, and reduction of oxidative stress were mediated by prenatal metformin, to prevent the development of hypertension
We demonstrated the presence of oxidative stress damage, represented by a greater 8-OHdG staining in the kidneys of male offspring exposed to high-fructose and high-fat diets, which was reduced by prenatal metformin therapy
Summary
Metformin (1,1-dimethylbiguanide hydrochloride) is the favorite first-line oral blood glucose-lowering treatment for type 2 diabetes [1]. The long-term effects of prenatal metformin exposure on offspring blood pressure (BP) have not been well studied. The Western diet, which is high in refined sugars and fat content, has been implicated in many diseases, including type 2 diabetes and hypertension. We previously reported that exposure to 60% HFR diet during pregnancy and lactation increased the risk of developing hypertension in adult offspring [10]. High-fat (HFA) diet has been used to generate animal models of hypertension and diabetes [11]. We found that post-weaning HFA diet exacerbates maternal HFR diet-induced programmed hypertension in adult offspring [12]. Whether prenatal metformin treatment can prevent combined prenatal HFR and post-weaning HFA diets-induced programmed hypertension in adult offspring much remains unknown
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