Research ArticleTargeting arachidonic acid pathway to prevent programmed hypertension in maternal fructose-fed male adult rat offspring
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-Δ12,14-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.
Section snippets
Experimental design
This study was approved by the Institutional Animal Care and Use Committee of the Kaohsiung Chang Gung Memorial Hospital. The protocol was carried out in strict accordance with the recommendations of National Institutes of Health guide for the care and use of Laboratory animals. Virgin Sprague–Dawley (SD) rats (BioLASCO Taiwan Co., Ltd., Taipei, Taiwan) were housed and maintained in a facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International
Morphological values and blood pressure
Litter sizes were not significantly altered by HF intake of the maternal rat (pups per litter: control=11.3±0.7; HF=11 9±0.9). We observed that pup mortality rates, BW and kidney weight were not different among the four groups (Table 1). The systolic BP and mean arterial pressure (MAP) of HF group were significantly higher than those in the control group at 12 weeks of age, which was prevented by AUDA therapy. As shown in Fig. 2, maternal HF exposure caused a marked increase in systolic BPs
Discussion
This study provides insight into a novel mechanism by which early target on arachidonic acid metabolism pathway prevents programmed hypertension in adult offspring exposed to maternal HF diet. The key findings in this study are the following: (1) early AUDA therapy prevents the increase of BPs in adult offspring exposed to maternal HF intake; (2) maternal HF-induced programmed hypertension is associated with increased renal protein level of SEH and oxidative stress, which AUDA therapy prevents;
Acknowledgments
This work was supported by Grants CMRPG8F0021 and CMRPG8C0043 from Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
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