Targeting arachidonic acid pathway to prevent programmed hypertension in maternal fructose-fed male adult rat offspring

Abstract

Hypertension can be programmed in response to nutritional insults in early life. Maternal high-fructose (HF) intake induced programmed hypertension in adult male offspring, which is associated with renal programming and arachidonic acid metabolism pathway. We examined whether early treatment with a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-Deoxy-Δ^12,14-prostagandin J₂ (15dPGJ₂) can prevent HF-induced programmed hypertension. Pregnant Sprague Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) during the whole period of pregnancy and lactation. Four groups of male offspring were studied: control, HF, HF+AUDA and HF+15dPGJ_2. In HF+AUDA group, mother rats received AUDA 25 mg/L in drinking water during lactation. In the HF+15dPGJ₂ group, male offspring received 15dPGJ₂ 1.5 mg/kg body weight by subcutaneous injection once daily for 1 week after birth. Rats were sacrificed at 12 weeks of age. Maternal HF-induced programmed hypertension is associated with increased renal protein level of SEH and oxidative stress, which early AUDA therapy prevents. Comparison of AUDA and 15dPGJ₂ treatments demonstrated that AUDA was more effective in preventing HF-induced programmed hypertension. AUDA therapy increases angiotensin converting enzyme-2 (ACE2) protein levels and PGE₂ levels in adult offspring kidney exposed to maternal HF. 15dPGJ₂ therapy increases plasma asymmetric dimethylarginine (ADMA) levels and decreases L-arginine-to-ADMA ratio. Better understanding of the impact of arachidonic acid pathway, especially inhibition of SEH, on renal programming may aid in developing reprogramming strategy to prevent programmed hypertension in children exposed to antenatal HF intake.

Introduction

The rising prevalence of hypertension globally has been linked to adaptation of western diets, especially fructose consumption [1]. Hypertension may be programmed in response to nutritional insults in early life [2]. While the fructose-fed rat has been used as an animal model of hypertension [3], very few studies have examined whether maternal fructose-fed adult offspring developed hypertension [4], [5], [6], [7], [8]. As kidney controls blood pressure (BP) and plays an important role on the development of hypertension, renal programming is considered a major mechanism driving programmed hypertension [9], [10], [11]. We reported previously that maternal high-fructose (HF) intake induced programmed hypertension in adult male offspring, which is associated with renal programming [6], [7], [8]. A number of mechanisms are proposed to be involved in renal programming and hypertension including activation of the renin–angiotensin system (RAS), nitric oxide (NO) deficiency, oxidative stress and alterations of sodium transporters [2], [9], [10], [11]. Using the RNA next generation sequencing (NGS) approach, our data implicated that arachidonic acid metabolism pathway is involved in maternal HF-induced programmed hypertension in the kidney [7].

Arachidonic acid can be metabolized by cytochrome P450 (CYP) epoxygenases to produce epoxyeicosatrienoic acids (EETs). EETs are metabolized by soluble epoxide hydrolase (SEH) to generate dihydroxyeicosatrienoic acids (DHETs) [12]. EETs are vasodilatory, while DHETs are vasoconstrictive. Our previous report showed that maternal HF increased renal 14,15-DHET level, a marker representing SEH activity in the 3-week-old offspring kidney [7]. Also, arachidonic acid can be metabolized by another pathway via cyclooxygenase (COX) isoenzymes to generate prostaglandin H₂ (PGH₂). Lipocalin-type prostaglandin D synthase (PGDS) can catalyze PGH₂ to produce PGD₂. As a consequence of a series of dehydration of PGD₂, a potent natural ligand of peroxisome proliferators-activated receptor gamma (PPARγ)–15-Deoxy-Δ^12,14-prostagandin J₂ (15dPGJ₂) is produced [13].

The plasticity during development implies a preventive strategy to shift the therapeutic approach from adult life to early stage, before hypertension is evident, a process namely reprogramming [14]. Given that SEH inhibitors and PPARγ agonists are potential therapies for hypertension [15], [16], and that arachidonic acid metabolism and PPAR signaling are two pathways identified by NGS involving in maternal HF-induced renal programming and hypertension [7], we aimed to elucidate whether early postnatal treatment targeting on arachidonic acid pathway with an SEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15dPGJ₂ can be reprogramming strategies to prevent programmed hypertension in the adult offspring exposed to maternal HF intake. Fig. 1 is a simple schematic summarizing main effects of AUDA and 15dPGJ₂ in the arachidonic acid pathway.