Abstract
Hypertension can originate from early-life adverse environmental in utero exposure to dexamethasone (DEX) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since DEX and TCDD are related to the aryl hydrocarbon receptor (AHR) signaling pathway, we examined whether resveratrol, an AHR modulator and antioxidant, could prevent programmed hypertension via regulating AHR signaling and oxidative stress. Groups of four-month-old male rat offspring were studied (n = 7–8 per group): control, DEX (0.1 mg/kg i.p. from a gestational age of 16 to 22 days), TCDD (200 ng/kg in four once-weekly oral doses), DEX + TCDD, and DEX + TCDD + R (resveratrol 0.05% in drinking water throughout pregnancy and lactation). Maternal TCDD exposure aggravated prenatal DEX-induced hypertension in adult male offspring, which maternal resveratrol therapy prevented. Maternal TCDD exposure aggravated DEX-induced oxidative damage in offspring kidneys, which was prevented by resveratrol therapy. Maternal resveratrol therapy decreased asymmetric and symmetric dimethylarginine (ADMA and SDMA) levels, thereby preventing combined DEX and TCDD exposure-induced programmed hypertension. Increases in renal Ahrr and Cyp1a1 expression induced by DEX + TCDD exposure were restored by resveratrol therapy. The beneficial effects of resveratrol on DEX + TCDD-induced hypertension relate to reduced renal mRNA expression of Ren, Ace, and Agtr1a expression. Thus, the beneficial effects of resveratrol on DEX + TCDD-induced hypertension include reduction of oxidative stress, restoration of nitric oxide (NO) bioavailability, blockade of the renin–angiotensin system (RAS), and antagonizing AHR signaling pathway.
Highlights
Hypertension is still a global health issue despite recent advances in pharmacotherapies
Since DEX and TCDD are related to the aryl hydrocarbon receptor (AHR) signaling pathway, we examined whether resveratrol, an AHR modulator and antioxidant, could prevent programmed hypertension via regulating AHR signaling and oxidative stress
Since each hit induced by prenatal DEX or TCDD exposure may act synergistically to deteriorate programming effects induced by each other, and because DEX and TCDD are closely linked to the AHR pathway, we postulate that maternal TCDD exposure could promote deleterious effects on prenatal DEX-induced renal programming and hypertension in adult offspring via the mediation of the AHR pathway in this two-hit model
Summary
Hypertension is still a global health issue despite recent advances in pharmacotherapies. The developing kidney is vulnerable to adverse early-life environments, which causes long-term morphological and functional changes, namely in renal programming [11]. Some particular mechanisms, such as nitric oxide (NO) deficiency, oxidative stress, and activation of the renin–angiotensin system (RAS), have been studied in terms of renal programming [11,12,13]. Given that resveratrol is considered as an AHR modulator [19] and an antioxidant, we examined whether maternal resveratrol treatment can protect offspring against combined TCDD and DEX exposure-induced hypertension of developmental origins via the regulation of oxidative stress, NO, RAS, and the AHR signaling pathway
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